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REVIEW ARTICLE
Splicing: is there an alternative contribution
to Parkinson’s disease?
Vale n t i n a L a C o gnata
1,3
&Velia D’Agata
3
&Francesca Cavalcanti
2
&
Sebastiano Cavallaro
1,2
Received: 8 January 2015 /Accepted: 4 May 2015
#The Author(s) 2015. This article is published with open access at Springerlink.com
Abstract Alternative splicing is a crucial mechanism of
gene expression regulation that enormously increases the
coding potential of our genome and represents an inter-
mediate step between messenger RNA (mRNA) transcrip-
tion and protein posttranslational modifications. Alterna-
tive splicing occupies a central position in the develop-
ment and functions of the nervous system. Therefore, its
deregulation frequently leads to several neurological hu-
man disorders. In the present review, we provide an up-
dated overview on the impact of alternative splicing in
Parkinson’s disease (PD), the second most common neu-
rodegenerative disorder worldwide. We will describe the
alternative splicing of major PD-linked genes by
collecting the current evidences about this intricate and
not carefully explored aspect. Assessing the role of this
mechanism on PD pathobiology may represent a central
step toward an improved understanding of this complex
disease.
Keywords Parkinson’s disease .Alternative splicing .
PD genes .mRNA splice transcripts .Protein isoforms
Introduction
The flow of genetic information from DNA to RNA to protein
has traditionally been considered the central dogma of molec-
ular biology. Additional steps of regulation are currently well
known, greatly expanding this simplistic framework and re-
vealing the complex network that controls gene expression
[1]. One of these steps is represented by alternative splicing
(AS), whereby a single gene gives rise to multiple messenger
RNA (mRNA) transcripts and protein isoforms with different
functional properties [1]. It is estimated that 94 % of human
protein-coding genes are alternatively spliced [2,3], and the
main site of alternative splicing events is the central nervous
system [4,5].
The alternative splicing process consists in the removal of
the intronic regions from the RNA primary transcript and si-
multaneous assembly of the exonic regions in different com-
binations to form a mature mRNA, which is then
polyadenilated, exported to the cytoplasm, and translated into
protein. The accuracy and efficiency of pre-mRNA splicing
process depend on a range of constitutive DNA sequence
motifs: the donor and the acceptor splice sites, the lariat
branch point, the polypyrimidine tract, and splicing enhancers
and silencers (Fig. 1, panel a). These motifs are recognized by
a large macromolecular splicing machinery (called the
spliceosome), which models the pre-mRNAwhile RNA poly-
merase II synthesizes it in the nucleus. The splicing machinery
includes five spliceosomal uridine-rich small nuclear ribonu-
cleoproteins (snRNPs) (U1, U2, U4, U5, and U6) and several
non-snRNP protein splicing factors such as the serine/arginine
(SR)-rich protein family and hnRNP proteins [6,7]. The splic-
ing reaction relies on two transesterification steps that occur
within the highly dynamic splicing machine. The stepwise
molecular mechanisms of the splicing reaction are detailed
in Fig. 1(panel a).
*Sebastiano Cavallaro
sebastiano.cavallaro@cnr.it
1
Institute of Neurological Sciences, Italian National Research
Council, Via Paolo Gaifami 18, 95125 Catania, Sicily, Italy
2
Institute of Neurological Sciences, Italian National Research
Council, 87050 Piano Lago di Mangone, Cosenza, Calabria, Italy
3
Department of Biomedical and Biotechnological Sciences, Section of
Human Anatomy and Histology, University of Catania, Catania, Italy
Neurogenetics
DOI 10.1007/s10048-015-0449-x
Alternative splicing works as an on–off switch in gene
expression. It affects the expression levels, stability, half-life
[via the nonsense-mediated mRNA decay (NMD)], and local-
ization of the RNA messengers. It has also the potential to
generate several protein isoforms with different biological
properties, protein–protein interactions, subcellular localiza-
tion, signaling pathway, or catalytic ability. During the last
years, great efforts have been made to decipher the intricate
alternative splicing code. Five major alternative splicing
events (i.e., cassette exons, use of alternative acceptor and/or
donor sites, intron retention, and mutually exclusive exons)
have been described up to now and are detailed in Fig. 1
(panel b) [2,8]. However, how the spliceosome recognizes
alternative exons and decides which exons to include remains
not fully understood. Undoubtedly, there is more diversity in
splice transcript variants than in protein isoforms. Although
this is still not clear, different variants encode the same pro-
tein, but probably translate it with different efficiencies [9].
The finely tuned splicing regulatory network can easily
undergo alterations. An aberrant alternative splicing may arise
from changes in regulatory sequences required for correct pre-
mRNA processing (the so-called cis-acting mutations), as well
as from mutations that affect components necessary for splic-
ing regulation (trans-acting mutations). Cis-andtrans-
splicing aberrations represent direct causative agents of dis-
ease or more subtle contributions to the determinants of dis-
ease susceptibility or modulators of disease severity. An ex-
tensive range of neurological diseases has been already asso-
ciated to both splicing defects, including Alzheimer’sdisease,
retinitis pigmentosa, spinal muscular atrophy, muscular dys-
trophy, neurofibromatosis, and fragile X-associated tremor/
ataxia syndrome [10–12,1,13]. In this broad neurological
disorder scenario, the relevance of alternative splicing in
Parkinson’s disease (PD) is not still clear, and the splicing
mechanisms that regulate PD-related genes remain mostly
unknown.
Here, we provide an updated overview of the current
knowledge about the impact of alternative splicing on
Parkinson’s disease. Firstly, we will take into account the most
common PD-related genes Bone by one^by analyzing their
alternative transcripts currently known and their involvement
in this disease. Then, we will describe the few studies that
have globally analyzed the changes of splice variant expres-
sion in PD patients through genome-wide RNA expression
approaches. Finally, we will briefly describe the current evi-
dences about the alternative splicing modulation in PD
through noncoding RNAs [microRNA (miRNA) and long
noncoding RNA (lcnRNA)].
Fig. 1 The alternative splicing mechanism. aFour main conserved DNA
sequence motifs allow the splicing mechanism: the donor splice site GU
(5′SS), the acceptor splice site AG (3′SS), the lariat branch point (A)
located upstream of the acceptor site and the polypyrimidine tract (PPT)
placed between the acceptor site and the branch point. The splicing
machinery includes mainly five spliceosomal uridine-rich small nuclear
ribonucleoproteins (snRNPs) (U1,U2,U4,U5,andU6) and further aux-
iliary RNA binding proteins. During the first step of spliceosome assem-
bly, U1 snRNP base pairs with the 5′splice site of the pre-mRNA (E
complex), whereas U2 base pairs with the branch point (A complex). Then
the tri-snRNP complex U4, U5, and U6 associates with the forming
spliceosome (B complex), and both U1 and U4 are ejected. This allows
U6 to replace U1 at the 5′splice site (C complex) and leads to a U6–U2
interaction that gets close together the 5′splice site and the branch point,
allowing for a transesterification step. At the end, U5 brings near the two
exons, joining them through a second transesterification reaction. bFive
major alternative splicing events are currently known: exon skipping/
inclusion, use of alternative 3′splice site, use of alternative 5′splice site,
mutually exclusive exons, and intron retention. In blue, are represented
the constitutive exons. Yellow and red represent the alternatively spliced
exons. The splicing events rely on the interplay between the constitutive
splicing motifs, the splicing regulatory sequences, the RNA secondary
structures, the components of the spliceosome, and further auxiliary
RNA-binding proteins. However, how the spliceosome decides which
exons to include remains currently not clear
Neurogenetics
Genetics of Parkinson’sdisease
PD is the second most common neurodegenerative disorder
worldwide, characterized by resting tremor, bradykinesia,
stiffness of movement, and postural instability. These symp-
toms are derived from the progressive loss of neurons from the
substantia nigra pars compacta, coupled with an accumula-
tion of intraneuronal aggregates called Lewy bodies.
Despite significant progresses in the understanding of PD
pathogenesis, the exact etiology of PD remains unknown.
Over the past 15 years, an even more detailed knowledge of
the genetic factors that contribute to PD has emerged through
different research strategies [14,15]. Linkage mapping analy-
sis, genome-wide association studies (GWAS), and next-
generation sequencing technologies are revealing an increas-
ing number of locus and genes strongly linked to either auto-
somaldominant(SNCA-PARK1,LRRK2-PARK8,VPS35-
PARK17, and GBA), or typical recessive (PARKIN-PARK2,
PINK1-PARK6,andDJ1-PARK7) and atypical recessive
(ATP13A2-PA R K 9 ,PLA2G6-PARK14,andFBXO7-PARK15)
or X-linked (ATP6A2 and TAF1) forms of disease. For the
sake of completeness, we mention here further monogenic
loci, not confirmed genes, or risk factor genes (i.e., PARK3,
UCHL1,PA R K 1 0 ,GIGYF2,PA R K 1 2 ,HTRA2,PA R K 1 6 ,
EIF4G1,DNAJ,HLA-DR,GAK-DGKQ,SYNJ1,andGBAP1)
[15–17]. Furthermore, a large-scale meta-analysis of genome-
wide association data is revealing a wide range of additional
loci having genome-wide significant association [18]. How-
ever, we will overlook their discussion because of the few data
in the literature regarding their splicing regulation in patho-
logical conditions.
In the next paragraphs, we will describe the alternative
spliced mRNAvariants of PD genes and the current scientific
data demonstrating their involvement in PD pathogenesis. For
a more complete picture, we have also added some further
implicated genes (SRRM2,MAO-B,SNCAIP,MAPT,and
GBA), indicated as other PD-related genes, which are not di-
rectly causative genes, but whose splicing regulation seems to
be altered in PD states.
Autosomal dominant PD genes
SNCA
Alpha-synuclein, encoded by SNCA gene, is a small, natively
unfolded presynaptic protein linked to PD [19]. Aggregates of
alpha-synuclein protein represent the neuropathological hall-
mark lesions of PD and constitute the major components of
Lewy bodies. Genetically, mutations in SNCA gene were the
first to be associated with PD family inheritance. Missense
mutations in coding regions (Ala53Thr, Ala30Pro, and
Glu46Lys), single nucleotide substitution in 3′untranslated
region (3′UTR), and dose-dependent genomic multiplications
(duplications or triplications) of the gene cause both mono-
genic and sporadic forms of PD [20,19,21]. Some point
mutations in splice donor sites have also been reported
(IVS2+ 9A>C) [22].
SNCA gene maps to chromosome 4q22.1 and contains six
exons spanning about 114 kb [21]. The set of mRNAs pro-
duced by SNCA gene includes the full-length transcript, com-
monly known as SNCA-140 from the amino acidic length of
the encoded protein, and corresponds to SNCA-001, SNCA-
002, SNCA-003, SNCA-006, and SNCA-008 mRNAs from
Ensembl library (Table 1and Fig. 2). Further additional splic-
ing variants, known as SNCA-126, SNCA-112, and SNCA-
98 and corresponding to (i) SNCA-004, SNCA-203, SNCA-
201, (ii) SNCA-005, SNCA-202, and (iii) SNCA-010, respec-
tively, are generated by in-frame excision of exons 3, 5, or
both (Table 1and Fig. 2). Two additional splice variants
(SNCA-009 and SNCA-007) are generated from an inner tran-
scription start and encode proteins of 115 and 97 amino acids,
respectively (Table 1and Fig. 2). SNCA-140, SNCA-126, and
SNCA-112 are expressed in a broad spectrum of human tis-
sues, while SNCA-98 seems to be a brain-specific splice var-
iant with varying expression levels in different areas of fetal
and adult brain [23].
The expression profile of SNCA-140, SNCA-126, SNCA-
112, and SNCA-98 splice variants is different in the various
brain areas under normal and pathological states. Compared to
healthy controls, in PD frontal cortex, all these four transcripts
are overexpressed, with significant upregulation of SNCA-
126 [24]. In PD substantia nigra, only the three shorter tran-
scripts have been observed significantly overexpressed [25,
26], while higher SNCA-112 and SNCA-98 levels are also
present in the cerebellum [25]. Different expression profiles
of SNCA variants also occur in other forms of neurodegener-
ative disorders. Both SNCA-140 and SNCA-126 downregu-
lation and SNCA-98 overexpression have been reported in
dementia with Lewy bodies and Alzheimer’sdisease,while
SNCA-112 is upregulated in dementia with Lewy bodies and
downregulated in Alzheimer’sdisease[27,28,24].
Some interesting data emerge on SNCA-112 variant. An
association between PD risk-associated single nucleotide
polymorphisms (SNPs) within the 3′region of SNCA gene
and higher SNCA-112 ratio level has been observed in about
100 of frontal cortex samples. These data reveal the cis-regu-
latory effect of these mutations on splicing mechanism [29].
The expression of SNCA-112 is also abundantly induced by
some parkinsonism mimetics (MPP+, rotenone) and related
oxidants [30]. However, the reason for these effects remains
unclear.
In addition to splice variants, specific RNA transcript iso-
forms of SNCA with an extended 3′untranslated region have
been described and appear selectively linked to pathological
processes [31]. However, this review is focusing only on the
mRNA splice variants; thus, their discussion will be omitted.
Neurogenetics
The 140 amino acid isoform is a small protein with a mo-
lecular weight of 14.5 kDa. It is composed of three distinct
regions: (1) an amino terminus containing amphipathic helices
conferring the propensity to bind membranes; (2) a central
hydrophobic region, the so-called non-Ab component
(NAC), which confers the b-sheet potential; and (3) an acid
glutamatergic carboxyl terminus that is highly negatively
charged and prone to be unstructured [19]. Structural changes
in the shorter splicing isoforms can be predicted as a result of
exon skipping events. SNCA-126-predicted isoform shows
interruption of the N-terminal protein–membrane interaction
domain [32]; SNCA-112 is significantly shorter in the un-
structured C-terminal [32], while SNCA-98 isoform results
in a truncated protein consisting almost only of the central
region containing NAC [23]. Recently, a lower aggregation
propensity of the shorter isoforms has been demonstrated
in vitro [33]. In addition, morphology studies by using elec-
tron microscopy have shown straight fibrils for SNCA-140,
shorter fibrils mostly arranged in parallel arrays for SNCA-
126, and circular structures for SNCA-98 [33]. These data
open new insights regarding the formation of Lewy bodies
induced by alpha-synuclein.
Numerous functions of alpha-synuclein have been pro-
posed, counting molecular chaperone, regulator of dopamine
uptake and homeostasis, inhibitor of phospholipase D2,
downregulator of p53 pathway [32],andpromoterofthe
SNARE-complex assembling [34]. Unfortunately, nothing is
known about the specific pathophysiological roles of each
alpha-synuclein isoform and their relative posttranslational
modifications (i.e., phosphorylations, nitration, sumoylation,
Tabl e 1 Alternative splice
variants of human autosomal
dominant PD genes
Gene name Transcript number Ensembl name Genbank accession number Protein length
SNCA 1. SNCA-003 NM_001146055 140 aa
2. SNCA-202 NM_007308 112 aa
3. SNCA-203 –126 aa
4. SNCA-201 –126 aa
5. SNCA-005 –112 aa
6. SNCA-001 NM_001146054 140 aa
7. SNCA-002 NM_000345 140 aa
8. SNCA-008 –140 aa
9. SNCA-006 –140 aa
10. SNCA-004 –126 aa
11. SNCA-010 –98 aa
12. SNCA-009 –115 aa
13. SNCA-007 –67 aa
LRRK2 1. LRRK2-002 –1271 aa
2. LRRK2-004 NM_198578 2527 aa
3. LRRK2-005 –207 aa
4. LRRK2-001 –521 aa
5. LRRK2-003 –No protein
6. LRRK2-006 –No protein
7. LRRK2-007 –No protein
VPS35 1. VPS35-001 NM_018206 796 aa
2. VPS35-002 –48 aa
3. VPS35-011 –No protein
4. VPS35-012 –No protein
5. VPS35-006 –No protein
6. VPS35-003 –No protein
7. VPS35-010 –No protein
8. VPS35-005 –47 aa
9. VPS35-008 –41 aa
10. VPS35-007 –No protein
11. VPS35-004 –No protein
Gene name, Ensembl transcript names, GenBank accession numbers, and relative encoded amino acidic protein
length of splice variants are reported in the table. Number in the column BTranscript number^identifies the
transcript in Fig. 2
Neurogenetics
oxidation, glycosylation, cleavage, and ubiquitination), which
are known to play a key role in SNCA functions and regula-
tion [32].
LRRK2
LRRK2 encodes for leucine-rich repeat kinase 2 (or dardarin),
which is a large 2527 amino acid multidomain protein. The
protein consists of multiple conserved well-defined domains
including a small GTPase-like domain (Ras of complex pro-
teins or ROC), a domain of unknown function termed the C-
terminal of ROC (COR), a kinase domain, as well as several
protein interaction domains [e.g., the leucine-rich repeat
(LRR), the WD40 domain, the ankyrin repeat domain, and
the armadillo repeat region]. The precise physiological func-
tion of LRRK2 is unknown. However, LRRK2 seems impli-
cated in different cellular functions as neurite outgrowth, cy-
toskeletal maintenance, vesicle trafficking, and autophagic
protein degradation [35].
The LRRK2 gene spans a genomic region of 144 kb, with
51 exons, and harbors the most common mutations linked to
both autosomal dominant inherited late-onset and sporadic
PD. The missense mutations known so far are spread over
the whole LRRK2 gene and affect all functional domains.
Some mutations have much higher frequencies than others,
such as Gly2019Ser and mutations altering codon Arg1441,
respectively, in the kinase and ROC domains. In addition,
several unclear pathogenic mutations affecting splice sites
have been observed (IVS19+5_8delGTAA, IVS25-8delT,
IVS27-9C>T, IVS30-6C> T, IVS31+3A> G, IVS32+ 14G>
A, IVS33+6 T>A, IVS37-9A>G, IVS38+7C>T, IVS46-
14 T> A, and IVS46-8delT) [36,22,37–43].
In addition to the full-length transcript (LRRK2-004), fur-
ther LRRK2 shorter transcripts are deposited in Ensembl li-
brary (Table 1and Fig. 2). Despite the existence of these
transcripts, there are currently no data analyzing the splicing
profile of this gene in PD states. Recently, a gene expression
and splicing analysis of the LRRK2 locus have been carried on
[44]. Both exon array and RT-PCR methods confirm the exis-
tence of an isoform with spliced out exons 32–33 in the
substantia nigra and an isoform with exon 32 alone spliced
out in the occipital cortex,medulla,andcerebellum of healthy
humans [44].
Further evidences on LRRK2 splicing have been observed
by Giesert and collaborators [45], who have conducted a study
in various brain regions and organs from adult mice. In this
regard, it should be considered that LRRK2 is highly con-
served in human and mouse and that several transgenic animal
models have been created. Giesert et al. [45] have identified
two LRRK2 splice variants: one with skipped exon 5, primar-
ily expressed in astrocytes, and another truncated variant ter-
minating with an alternative exon 42a barely detectable in the
microglia but highly expressed in neurons and astrocytes.
Protein-structure predictions reveal that the loss of exon 5
may generate a smaller protein with changed affinity of bind-
ing partners, while the alternative exon 42a may leadto chang-
es of its enzymatic activity. In addition, the protein-interaction
domain WD40 would also be absent in such truncation.
Fig. 2 Structures of the
alternative splicing variants of
human dominant PD genes.
Structures of the described
mRNA splicing variants are
represented in the figure as
reported in Ensembl library
(http://www.ensembl.org/index.
html). On the left, each variant is
indicated with a number
corresponding to that indicated in
Tab le 1.LRRK2 gene is illustrated
in 5′-3′sense, while SNCA and
VPS35 genes are illustrated in
antisense corresponding to their
3′-5′sense transcription
Neurogenetics
Interestingly, the deletion of this domain in the Zebrafish
LRRK2 ortholog (zLRRK2) causes parkinsonism-like pheno-
type including loss of dopaminergic neurons in diencephalon
and locomotion defects [46]. Further studies will need to as-
sess the involvement of LRRK2 alternative splice variants in
PD.
VPS35
In 2011, two groups reported the identification of the same
missense mutation (p.Asp620Asn) in the vacuolar protein
sorting 35 (VPS35) gene as a novel cause of autosomal dom-
inant PD [47,48]. VPS35 was the first PD gene found by a
direct whole exome sequencing in large families of Austrian
and Swiss origins. An in-depth sequence analyses of all cod-
ing, noncoding, and exon–intron boundaries VPS35 genetic
regions have been performed in a large well-characterized
cohort of Lewy body disorders, including PD patients, PD
with dementia, and dementia with Lewy bodies [49]. In addi-
tion to three novel missense mutations, silent and intronic
variations, predicted to activate cryptic splice sites, have been
observed in the patient’s group but not in controls. However,
the pathogenicity of these mutations was not completely con-
clusive since these mutations were not supported by segrega-
tion analysis in family relatives [49].
Various spliced transcript variants of this gene are reported
in Ensembl library (Table 1and Fig. 2), but the majority of
them are processed for degradation and do not encode
proteins.
Autosomal recessive PD genes
Early-onset typical PD genes
PARK2 Mutations in PA R K 2 gene (also known as PA R K 2
parkin RBR E3 ubiquitin-protein ligase) are the most common
cause (50 % of cases) of autosomal recessive juvenile parkin-
sonism (AR-JP), a form of early-onset parkinsonism charac-
terized by good and prolonged response to levodopa and a
benign, slow course. PA R K 2 mutations also explain ~15 %
of the sporadic cases with onset before 45 [50,51] and act
as susceptibility alleles for late-onset forms of Parkinson’s
disease (2 % of cases) [52]. Along with about 200 mutations
currently identified in PARK2 coding region, several point
mutations in splice acceptor or donor sites (introns 1, 6, 7,
10, 12, 13, and 16) have been identified in PD patients
[53–57,22,58,59].
PA R K 2 gene spans more than 1.38 Mb of genomic DNA in
the long arm of chromosome 6 (6q25.2–q27) and contains 12
exons, which are alternatively spliced to produce at least 11
different splicing variants (Table 2and Fig. 3)[59]. The full-
length PA R K 2 transcript (PARK2-004) encodes a protein of
465 amino acids (parkin) [60,61,59] acting in numerous
molecular pathways (protein turnover, stress response, mito-
chondrial homeostasis, mitophagy, mitochondrial DNA stabil-
ity, metabolism, cell growth, and survival) [62]. Multiple
parkin isoforms likely arising from PAR K 2 splicing variants
have been observed in different brain areas through Western
blot studies [9].
The extensive alternative splicing of PARK2 is differently
regulated both at transcript and protein level in tissues and cells
[63,64,24,65–68]. Distinct expression patterns of PA RK 2
splice variants emerge in human brain regions [69] and leuko-
cytes [68], in rat brain, in neuronal and glial cells [67],andina
wide variety of mouse tissues (brain, heart, lung, liver, skeletal
muscle, kidney, and testis) [64]. At the protein level, PA R K 2
protein isoforms show a differential distribution in human leu-
kocytes [70] and aged brain [71], as well as in different rat and
mouse nervous system areas (cerebral cortex/diencephalons,
hippocampus, cerebellum, brainstem, striatum, spinal cord,
and substantia nigra), peripheral tissues (heart, liver, spleen,
pancreas, and kidney), and developmental stages [72–76].
Emerging evidences support the importance of PARK2
splice variant expression changes in disease development.
Differential expression of PARK2 transcripts have been iden-
tified in the frontal cortex of Parkinson’sdisease,puredemen-
tia with Lewy bodies, common Lewy body disease, and
Alzheimer’s disease patients, compared to controls [65,24].
Particularly, two PARK2 splicing variants are significantly
overexpressed in PD [65]. Another study reports both an in-
crease in the expression level of a parkin splice variant and a
decrease of the wild type between PD patients and healthy
controls [66]. The differential and disease-specific expression
profiles of PA R K 2 alternative splice variants suggest a role for
splicing deregulation in the development of neurodegenera-
tive disorders.
PINK1 Homozygous or compound heterozygous loss-of-
function mutations in PTEN-induced putative kinase 1
(PINK1) are the second most frequent cause of autosomal
recessive early-onset parkinsonism. Mutation frequency
varies geographically from 1 to 9 % depending on ethnic
background [77]. The PINK1 mutation spectrum involves
nonsense and missense mutations, insertions, or deletions,
and whole gene or single/multiple exon copy number variants
located across the entire gene [78].
PINK1 gene maps in the short arm of chromosome 1
(1p36.12), encompassing ~18 kb of genomic DNA. Its coding
sequence is spread over eight exons. In addition to the full
length (PINK1-001), two shorter variants exist but do not
produce proteins (Table 2and Fig. 3).
Some interesting findings emerge regarding the splicing
regulation of exon 7. A 23-bp deletion disrupting the splice
acceptor site of exon 7 has been detected in a sporadic parkin-
sonian patient, producing several aberrant mRNAs [79].
Moreover, whole exon 7 deletion and a novel U1-dependent
Neurogenetics
5′splice-site mutation in exon 7 have been found in a large
Spanish family with PD members [80].
The PINK1 protein is a putative serine/threonine kinase of
581 amino acids involved in mitochondrial response to cellu-
lar and oxidative stress [81]. It has been demonstrated that at
least two isoforms are expressed in the human brain: a full-
length protein of ~63 kDa and an N-terminally truncated iso-
form of 52 kDa [77,82–84]. An additional isoform of approx-
imately 45 kDa has been suggested, although it has not been
extensively studied [85]. The 52-kDa isoform seems to orig-
inate by enzymatic cleavage of PARL [86]; however, the exact
nature of the isoforms, the precise reason for the cleavage, and
the functional roles of these three different isoforms require
further studies.
Tabl e 2 Alternative splice variants of human autosomal recessive PD
genes
Gene
name
Transcript
number
Ensembl name Genbank accession
number
Protein
length
PA R K 2 1. PARK2-004 NM_004562 465 aa
2. PARK2-005 NM_013987 437 aa
3. PARK2-006 NM_013988 316 aa
4. PARK2-001 –274 aa
5. PARK2-003 –274 aa
6. PARK2-007 –218 aa
7. PARK2-201 –176 aa
8. PARK2-204 –87 aa
9. PARK2-002 –368 aa
10. PARK2-202 –74 aa
11. PARK2-203 –201 aa
PINK1 1. PINK1-001 NM_032409 581 aa
2. PINK1-002 –No protein
3. PINK1-003 –No protein
DJ1 1. PARK7-004 –189 aa
2. PARK7-002 NM_001123377;
NM_007262
189 aa
3. PARK7-007 –No protein
4. PARK7-001 –189 aa
5. PARK7-003 –169 aa
6. PARK7-008 –No protein
7. PARK7-005 –189 aa
8. PARK7-006 –189 aa
9. PARK7-009 –No protein
10. PARK7-010 –160 aa
ATP13A2 1. ATP13A2-001 NM_022089 1180 aa
2. ATP13A2-002 NM_001141974 1158 aa
3. ATP13A2-005 NM_001141973 1175 aa
4. ATP13A2-004 –No protein
5. ATP13A2-003 –No protein
6. ATP13A2-010 –191 aa
7. ATP13A2-007 –398 aa
8. ATP13A2-014 –258 aa
9. ATP13A2-009 –321 aa
10. ATP13A2-006 –No protein
11. ATP13A2-201 –228 aa
12. ATP13A2-013 –No protein
13. ATP13A2-011 –190 aa
14. ATP13A2-012 –191 aa
15. ATP13A2-008 –188 aa
PLA2G6 1. PLA2G6-001 NM_003560 806 aa
2. PLA2G6-201 NM_001004426 752 aa
3. PLA2G6-002 NM_001199562 752 aa
4. PLA2G6-025 –No protein
5. PLA2G6-021 –No protein
6. PLA2G6-014 –166 aa
7. PLA2G6-024 –No protein
8. PLA2G6-013 –No protein
Tabl e 2 (continued)
Gene
name
Transcript
number
Ensembl name Genbank accession
number
Protein
length
9. PLA2G6-026 –168 aa
10. PLA2G6-015 –120 aa
11. PLA2G6-010 –99 aa
12. PLA2G6-023 –226 aa
13. PLA2G6-009 –No protein
14. PLA2G6-027 –51 aa
15. PLA2G6-022 –No protein
16. PLA2G6-012 –151 aa
17. PLA2G6-019 –124 aa
18. PLA2G6-011 –No protein
19. PLA2G6-020 –No protein
20. PLA2G6-008 –No protein
21. PLA2G6-016 –229 aa
22. PLA2G6-005 –99 aa
23. PLA2G6-018 –157 aa
24. PLA2G6-003 –99 aa
25. PLA2G6-017 –197 aa
26. PLA2G6-007 –80 aa
27. PLA2G6-004 –No protein
28. PLA2G6-006 –No protein
FBXO7 1. FBXO7-003 –41 aa
2. FBXO7-001 NM_012179 522 aa
3. FBXO7-004 –49 aa
4. FBXO7-005 –No protein
5. FBXO7-006 –129 aa
6. FBXO7-002 NM_001033024;
NM_001257990
408 aa
7. FBXO7-007 –54 aa
8. FBXO7-008 –No protein
9. FBXO7-010 –No protein
Gene name, Ensembl transcript names, GenBank accession numbers, and
relative encoded amino acidic protein length of splice variants are report-
ed in the table. Number in the column BTranscript number^identifies the
transcript in Fig. 3
Neurogenetics
DJ1 Mutations in the DJ1 (also known as PA R K 7 )geneare
the less common cause of autosomal recessive parkinsonism
(~1 % of early-onset PD) [87,88]. A large homozygous dele-
tion and a missense mutation (L166P) in DJ-1gene were first
identified in both Italian and Dutch consanguineous families
[89,90]. Additional mutations have been collected in other
PD families and include missense mutations in coding and
promoter regions, frame shifts, copy number variations [91,
88], and splice site alterations [92,93].
DJ-1gene maps to chromosome 1 (1p36.23) and includes
seven exons. Several spliced transcript variants have been
identified encoding the same protein (Table 2and Fig. 3).
Two shorter transcripts (the first lacking exon 4 and the second
starting in an inner transcription point) encode for smaller
proteins (Table 2and Fig. 3).
The product of DJ-1gene is a highly conserved protein of
189 amino acids belonging to the peptidase C56 family [94]. It
is a multifunctional protein, acting as a positive regulator of
transcription, redox-sensitive chaperone, sensor for oxidative
stress, and apparently protects neurons from ROS-induced
apoptosis [95,96]. In the human brain and peripheral blood,
several DJ-1isoforms exist and differ on their isoelectric point
(pI)[97–100]. The relative abundance of these different DJ-1
isoforms appears to be altered in PD, and therefore, blood DJ-
1isoforms have been proposed as potential biomarkers for
Parkinson’s disease [101]. The different pI of each variant
are believed to result from posttranslational modifications that
alter the intrinsic charge of the protein [101]. Interestingly, it
has been demonstrated that one of the major binding partners
of DJ-1 in dopaminergic neuronal cells is the splicing factor
proline/glutamine-rich (SFPQ protein) [96,102]. SFPQ, orig-
inally identified as a polypyrimidine tract-binding protein, is
part of the spliceosome C complex and is required for in vitro
splicing of pre-mRNA [96,102]. DJ-1 binding to SFPQ mod-
ulates its transcriptional activity and, therefore, tunes its effect
on splicing regulation. DJ-1 mutations could reverberate on its
downstream targets, including the splicing factor SFPQ and
altering the splicing control.
Juvenile atypical PD genes
ATP13A2 ATP13A2 mutations are associated with Kufor–
Rakeb syndrome, a form of recessively levodopa-responsive
inherited atypical parkinsonism [103]. It encodes a large pro-
tein belonging to the ATPase transmembrane transporters, and
recently, it has been identified as a potent modifier of the
toxicity induced by alpha-synuclein [104].
ATP13A2 is composed of 29 exons and lies on chromo-
some 1 covering about 26 kb of genomic DNA. One of the
first identified disease-causing mutations was a guanine-to-
adenine transition in the donor splice site of exon 13, leading
to the skipping of exon 13 and resulting in a deletion of part of
the third transmembrane domain [105].
According to data repositories, at least 15 alternatively
spliced transcripts are expressed in humans (Table 2and
Fig. 3). The longest transcripts are ATP13A2-001,
ATP13A2-002, and ATP13A2-005. Transcript variants
ATP13A2-001 and ATP13A2-005 differ only in a nucleotide
segment on exon 5, while transcript variant ATP13A2-002
lacks exons 22 and 28. The ATP13A2 mRNA is highly
Fig. 3 Structures of the alternative splicing variants of human recessive
PD genes. Structures of the described mRNA splicing variants are
represented in the figure as reported in Ensembl library (http://www.
ensembl.org/index.html). On the left, each variant is indicated with a
number corresponding to that indicated in Table 2. All transcripts are
illustrated in 5′-3′sense, except PA R K 2 ,ATP13A2,andPLA2G6 genes,
which are illustrated in antisense corresponding to their 3′–5′sense
transcription
Neurogenetics
expressed in the brain, particularly in the substantia nigra of
patients with classical late-onset PD [91]. However, nothing is
known about the splicing expression profiles of this gene in
PD and healthy subjects.
The products of these transcripts have been studied at the
protein level. The isoform 1 encoded by ATP13A2-001 is a
protein of 1180 amino acids with ten transmembrane domains.
Isoform 2 encoded by ATP13A2-005 contains a five amino
acid deletion near the N-terminus, while isoform 3, encoded
by ATP13A2-002, contains two deletions, generating a highly
diverged C-terminus [105]. Functional studies have shown
that the isoform 1 is located in the lysosome membrane,
whereas the isoform 3 protein is retained in the endoplasmic
reticulum and rapidly degraded by the proteasome. In addi-
tion, both isoforms 1 and 3 are eliminated via the endoplasmic
reticulum-associated degradation pathway [105].
PLA2G6 Recessive mutations in the phospholipase A2
group VI (PLA2G6) gene have been initially described
as the cause of infantile neuroaxonal dystrophy and neu-
rodegeneration associated with brain iron accumulation.
Recently, this gene has also been associated with a partic-
ular parkinsonian phenotype, consisting of levodopa-
responsive dystonia, pyramidal signs, and cognitive/
psychiatric features, with onset in early adulthood [106].
Among PLA2G6 identified mutations, the c.1077G>A
mutation at the last nucleotide of exon 7 (apparently a
synonymous mutation) stands out as a cause of abnormal
mRNA splicing. This single nucleotide substitution causes
the activation of a cryptic splice site producing a 4-bp
deleted transcript with altered frame shift in leukocytes
[106].
PLA2G6 gene maps on chromosome 22 (q13.1), covering
70 kb of genomic DNA. Several transcript variants encoding
multiple isoforms have been described up to now (Table 2and
Fig. 3). The longest PLA2G6 mRNA PLA2G6-001 includes
17 exonic regions and encodes the 85/88 kDa calcium-
independent phospholipase known as A2 isoform a. The other
Tabl e 3 Alternative splice
variants of human X-linked PD
genes
Gene name Transcript number Ensembl name Genbank accession number Protein length
TAF 1 1. TAF1-201 NM_001286074 1895 aa
2. TAF1-009 NM_138923 1872 aa
3. TAF1-008 NM_004606 1893 aa
4. TAF1-014 –458 aa
5. TAF1-010 –490 aa
6. TAF1-021 –No protein
7. TAF1-011 –No protein
8. TAF1-013 –No protein
9. TAF1-012 –No protein
10. TAF1-015 –No protein
11. TAF1-018 –No protein
12. TAF1-016 –No protein
13. TAF1-022 –No protein
14. TAF1-023 –No protein
15. TAF1-005 –No protein
16. TAF1-006 –No protein
17. TAF1-020 –No protein
18. TAF1-019 –No protein
19. TAF1-017 –279 aa
20. TAF1-007 –150 aa
ATP6AP2 1. ATP6AP2-004 NM_005765 350 aa
2. ATP6AP2-007 –203 aa
3. ATP6AP2-005 –No protein
4. ATP6AP2-006 –243 aa
5. ATP6AP2-001 –259 aa
6. ATP6AP2-003 –No protein
7. ATP6AP2-002 –No protein
Gene name, Ensembl transcript names, GenBank accession numbers, and relative encoded amino acidic protein
length of splice variants are reported in the table. The number in the column BTranscript number^identifies the
transcript in Fig. 4
Neurogenetics
two long transcripts (PLA2G6-002 and PLA2G6-201) differ
in the start point, both lack of exon 9 and encode the same
protein, called isoform b. The expression profile of this gene
in healthy and disease states remains unknown.
FBXO7 Mutations in the F-box only protein 7 (FBXO7)
gene cause parkinsonian pyramidal disease (PPD- or
PARK15-associated parkinsonism), an autosomal reces-
sive neurodegenerative disease with juvenile onset, se-
vere levodopa-response, and additional pyramidal signs.
Some pathogenic mutations have been identified
(R378G, R498X, and T22M) including a compound het-
erozygous mutation (IVS7+1G/T) that removes the in-
variable splice donor of intron 7 and may disrupt FBXO7
messenger RNA splicing [107–109].
The FBXO7 gene, mapped on chromosome 22q12.3, con-
tains nine exons spanning about 24.1 kb. It encodes a 522
amino acid protein consisting ofseveral domains [108], which
target proteins for ubiquitination [108]. Alternatively spliced
transcript variants of this gene have been identified (Table 2
and Fig. 3)[107]. FBXO7-001 is the longest and more abun-
dant transcript ubiquitously expressed [110], particularly in
skin fibroblasts [111]. FBXO7-002 arises from an inner alter-
native exon 1,differs in the start codon, and produces a shorter
isoform. Both these encoded protein isoforms have been de-
tected in cells [111].
X-linked parkinsonism
X-linked dystonia parkinsonism (XDP) is an X-linked reces-
sive adult-onset movement disorder characterized by both
dystonia and parkinsonism. TATA-box binding protein-associ-
ated factor 1 (TAF1) gene, located in the disease locus
Xq13.1, has been reported as the first related XPD gene, har-
boring disease-specific single-nucleotide changes and a small
deletion within the multiple transcript panel [112]. This gene
is part of a complex region of DNA (the TAF1/DYT3 multiple
transcript systems), which encompasses the exonic regions of
TAF1 gene and further additional downstream exons [112,
113]. This system includes multiple different transcription
start sites and encodes multiple spliced transcripts and iso-
forms (Table 3and Fig. 4)[112].
Recently, the ATP6AP2 gene (Table 3and Fig. 4) has been
proposed as a novel gene for X-linked parkinsonism with
spasticity (XPDS) by exome sequencing analysis [114]. A
silent mutation (p.S115S) in the ATP6AP2 gene has been
identified in one affected individual, resulting in the aberrant
splicing of ATP6AP2 mRNA and the overexpression of a
minor splice isoform [114]. Noteworthy, the ATP6AP2 is an
essential accessory component of the vacuolar ATPase re-
quired for lysosomal degradative functions and autophagy, a
pathwayfrequentlyaffectedinPD.
Other PD-related genes
SNCAIP
Synphilin-1, encoded by SNCAIP gene, is a presynaptic pro-
tein containing several protein–protein interaction motifs, in-
cluding ankyrin-like repeats, a coiled-coil domain, and an
ATP/GTP-binding domain [115]. It interacts strongly with
alpha-synuclein in neuronal tissue and may play a role in the
formation of Lewy bodies during neurodegeneration. It is also
implicated in parkinsonism as one of the parkin substrates. In
addition, some studies have identified SNCAIP sequence var-
iants in PD patients and have suggested it as a candidate PD
gene [116,117].
SNCAIP gene maps on chromosome 5 (5q23.2) and
spans about 152 kb of genomic DNA. Although the data-
base Gene reports SNCAIP composed of 11 exons, addi-
tional exonic regions emerge by aligning the sequence of
the gene with each transcript. To date, at least 22 alterna-
tive spliced transcript variants have been identified
(Table 4and Fig. 5), but the most studied are synphilin-1
and 1A. Synphilin-1 (SNCAIP-001) is the full-length tran-
script, while synphilin-1A variant is a shorter form
(SNCAIP-201). The latter lacks exons 4 and 5 and contains
an extra exon located between exons 10 and 11. Synphilin-
1A isoform is thought to be involved in the pathogenesis of
PD and may play an important role in the formation of
Lewy bodies [118–120]. Interestingly, synphilin-1A pro-
tein shows enhanced aggregation properties, which cause
neuronal toxicity [118–120].
Fig. 4 Structures of the alternative splicing variants of human X-linked
PD genes. Structures of the described mRNA splicing variants are repre-
sented in the figure as reported in Ensembl library (http://www.ensembl.
org/index.html). On the left, each variant is indicated with a number
corresponding to that indicated in Table 3. All transcripts are illustrated
in 5′-3′sense
Neurogenetics
The mRNA expression levels of synphilin 1, 1A, and other
two additional synphilin variants have been simultaneously
Tabl e 4 Alternative splice variants of other human PD-related genes
Gene
name
Transcript
number
Ensembl name Genbank accession
number
Protein
length
SNCAIP 1. SNCAIP-019 –135 aa
2. SNCAIP-003 –66 aa
3. SNCAIP-016 –161 aa
4. SNCAIP-017 –98 aa
5. SNCAIP-010 –858 aa
6. SNCAIP-001 NM_005460 919 aa
7. SNCAIP-204 –113 a a
8. SNCAIP-201 NM_001242935 603 aa
9. SNCAIP-004 –66 aa
10. SNCAIP-018 –68 aa
11. SNCAIP-002 –1016 aa
12. SNCAIP-006 –62 aa
13. SNCAIP-005 –No protein
14. SNCAIP-007 –66 aa
15. SNCAIP-203 –88 aa
16. SNCAIP-202 –62 aa
17. SNCAIP-012 –66 aa
18. SNCAIP-011 –88 aa
19. SNCAIP-009 –588 aa
20. SNCAIP-008 –113 aa
21. SNCAIP-015 –14 aa
22. SNCAIP-013 –No protein
MAO-B1. MAOB-001 NM_000898 520 aa
2. MAOB-002 –No protein
3. MAOB-004 –No protein
GBA 1. GBA-011 –No protein
2. GBA-001 NM_000157 536 aa
3. GBA-002 NM_001005741;
NM_001005742
536 aa
4. GBA-003 –No protein
5. GBA-009 –No protein
6. GBA-015 NM_001171812 487 aa
7. GBA-016 NM_001171811 449 aa
8. GBA-005 –No protein
9. GBA-012 –No protein
10. GBA-006 –No protein
11. GBA-010 –No protein
12. GBA-014 –No protein
13. GBA-007 –No protein
14. GBA-013 –No protein
MAPT 1. MAPT-204 NM_005910 441 aa
2. MAPT-202 NM_001123067 412 aa
3. MAPT-201 NM_016835 758 aa
4. MAPT-205 NM_001203251;
NM_001203252
410 aa
5. MAPT-203 NM_001123066 776 aa
6. MAPT-013 –No protein
7. MAPT-001 NM_016841 352 aa
8. MAPT-002 NM_016834 383 aa
Tabl e 4 (continued)
Gene
name
Transcript
number
Ensembl name Genbank accession
number
Protein
length
9. MAPT-006 –410 aa
10. MAPT-007 –441 aa
11. MAPT-008 –758 aa
12. MAPT-004 –776 aa
13. MAPT-003 –412 aa
14. MAPT-009 –341 aa
15. MAPT-014 –No protein
16. MAPT-011 –59 aa
17. MAPT-010 –No protein
18. MAPT-012 –No protein
SRRM2 1. SRRM2-001 NM_016333 2752 aa
2. SRRM2-201 –311aa
3. SRRM2-003 –1018 aa
4. SRRM2-006 –297 aa
5. SRRM2-004 –No protein
6. SRRM2-007 –895 aa
7. SRRM2-011 –No protein
8. SRRM2-028 –94 aa
9. SRRM2-012 –115 aa
10. SRRM2-013 –251 aa
11. SRRM2-029 –No protein
12. SRRM2-014 –No protein
13. SRRM2-030 –No protein
14. SRRM2-015 –No protein
15. SRRM2-016 –No protein
16. SRRM2-017 –No protein
17. SRRM2-009 –No protein
18. SRRM2-018 –No protein
19. SRRM2-019 –No protein
20. SRRM2-022 –No protein
21. SRRM2-020 –184 aa
22. SRRM2-021 –No protein
23. SRRM2-023 –No protein
24. SRRM2-024 –No protein
25. SRRM2-025 –No protein
26. SRRM2-026 –No protein
27. SRRM2-010 –No protein
28. SRRM2-027 –No protein
29. SRRM2-031 –78 aa
30 SRRM2-032 –41 aa
31. SRRM2-033 –No protein
Gene name, Ensembl transcript names, GenBank accession numbers and
relative encoded amino acidic protein length of splice variants are report-
ed in the table. Number in the column BTranscript number^identifies the
transcript in Fig. 5
Neurogenetics
investigated in the frontal cortex of PD patients. Their overall
overexpression has been demonstrated when compared to
healthy controls [24,65].
MAPT
MAPT gene encodes the microtubule-associated protein tau, a
protein involved in microtubule assembly and stability [121].
It is located on chromosome 17q21 and contains 15 exons. It
gives rise to multiple splice transcripts (Table 4and Fig. 5)
which are differentially expressed in human tissues [11]. In the
adult human central nervous system, MAPT splicing generates
six tau isoforms composed of either three or four microtubule-
binding repeat motifs in the C-terminal (3R- and 4R-tau).
A number of mutations within and around MAPT exon 10
disrupt exonic and intronic splicing elements as well as the
formation of an RNA stem-loop structure at the 5′splice site
(which normally functions to restrict spliceosome assembly).
This event results in an altered ratio of 3R/4R isoforms [10,
13]. The disruption of the balance between them results in
hyperphosphorylation and aggregation of tau proteins into
neurofibrillary tangles, causing the frontotemporal dementia
with parkinsonism linked to chromosome 17 (FTDP-17) [10,
13]. These data support a direct relationship between aberrant
alternative splicing of tau and neuropathology.
GBA
Mutations in β-glucocerebrosidase (GBA) gene cause Gauch-
er disease, a lysosomal storage disease characterized by an
accumulation of glucocerebrosides. Some studies have iden-
tified GBA genetic variants as significant risk factors for the
development of PD [122,15].
GBA gene is located in a gene-rich region on chromosome
1q21. It spans 10.4 kb and contains 12 exons. Currently, there
are four annotated alternative transcripts encoding proteins
(GBA-001, GBA-002, GBA-015, and GBA-016; Table 4
and Fig. 5). Two of them originate from an alternative
Fig. 5 Structures of the alternative splicing variants of the other human
PD-related genes. Structures of the described mRNA splicing variants are
represented in the figure as reported in Ensembl library (http://www.
ensembl.org/index.html). On the left, each variant is indicated with a
number corresponding to that indicated in Table 4. All transcripts are
illustrated in 5′-3′sense, except MAO-Band GBA genes, which are
illustrated in antisense corresponding to their 3′-5′sense transcription
Neurogenetics
promoter located 2.6 kb upstream of the first ATG [123]. All
transcripts share the same start codon, with the exception of
GBA-012, whose open-reading frame starts upon exon 4 and
produces a shorter protein isoform. Further transcripts are pro-
duced, but they do not encode proteins. The GBA splicing
profile has not been studied still, and it is unknown if its
alternative splicing is involved in PD.
MAO-B
MAO-Bgene is located on chromosome X and includes 15
exons (Table 4and Fig. 5). Although it is not a confirmed
susceptibility gene [18], increased levels of monoamine oxi-
dase B (MAO) mRNA and enzymatic activity have been re-
ported in platelets from patients with both Parkinson’s and
Alzheimer’s diseases [124]. Furthermore, it is well established
that MAO-B inhibitors delay progression of both pathologies
[125,126].
Several DNA polymorphisms in the MAO-Bgene have
been described in populations with distinct ethnic back-
grounds [124]. A SNP common in all ethnic groups and asso-
ciated with two-fold risk of PD is the G/A dimorphism in
intron 13 sequence [127–129]. This SNP does not change
the coding sequence and does not affect the consensus accep-
tor and donor sites. However, it has been demonstrated the G/
A dimorphism in intron 13 sequence creates a splicing en-
hancer that stimulates intron 13 removal and a spliceosomal
complex assembly and alters splicing factors’binding site
efficiency [124].
SRRM2
Along with cis-acting elements, alternative splicing regulation
relies on trans-splicing factors including the serine/arginine
(SR) proteins. One of these proteins, the RNA splicing factor
SRRM2 (or serine/arginine repetitive matrix 2), has been iden-
tified as the only gene that stood out as differentially expressed
in multiple gene expression PD datasets [130].
SRRM2 gene generates two main alternative splicing tran-
scripts different at their 3′end (Table 4and Fig. 5). The full-
length isoform SRRM2-001 contains 15 exons, while the
shorter isoform SRRM2-003 contains 11 exons and lacks
exons 12–15. These two isoforms are differentially expressed
in postmortem PD brain regions [130]. The shorter transcript
was upregulated in the substantia nigra but unchanged in the
amygdala of PD patients versus healthy controls. On the con-
trary, the longer transcript was downregulated in both
substantia nigra and amygdala of PDs as compared to con-
trols [130]. Furthermore, in the peripheral blood of patients
with PD, SRRM2 short isoform is overexpressed, while the
expression of longest isoform is reduced [130].
Genome-wide RNA expression analysis reveals
global alternative splicing changes in PD
Although a Bgene-by-gene^approach may simplify splicing
analysis, global alternative splicing changes in PD have to be
considered. The majority of the whole gene expression array
studies in PD brain regions have unfortunately looked at a
single transcript per gene, ignoring the multiple transcripts
generated by alternative splicing [14]. Nonetheless, mRNA
splicing has been identified as a mechanism significantly al-
tered in cortical neurons of PD patients [131].
In order to investigate the splicing expression changes,
some studies have used exon arrays. This kind of approach,
enabling better monitoring and detection of the alternative
splicing events, has allowed to observe significant changes
in overall gene splicing in PD blood cells compared to healthy
controls [130,132]. Another exon array study has been con-
ducted in blood of advanced PD patients prior to and follow-
ing deep brain stimulation neurosurgery, a technique that effi-
ciently improves the motor symptoms of PD [133]. This anal-
ysis has showed preliminary results suggesting brain electrical
stimulation may correlate with significant profile changes in
nonsense-mediated mRNA decay (an mRNA surveillance
process that detects and selectively degrades splice transcripts
harboring premature termination codons) in blood cell tran-
scripts [133]. Potashkin et al. [134]havealsousedspecific
splice variant microarrays in PD patients in order to identify
mRNAs splice transcripts as molecular biomarkers for an ear-
ly PD diagnosis. Through this approach, they identified 13
splice variants with an altered expression in early-stage PD
patients versus healthy controls [134,135].
A recent technology to better study splicing defects is deep
sequencing of RNA (RNAseq) [14]. The advantage of
RNAseq is that it is theoretically feasible to measure both
RNA expression levels and modifications such as splicing.
In addition, RNAseq gives the possibility of discovering novel
transcripts. Whole transcriptome RNAseq data have been ob-
tained from blood leukocytes of PD patients’predeep and
postdeep brain stimulation treatment [136]. This approach
has enabled to discover novel human exons and junctions in
protein-coding RNA molecules, as well as a large range of
differential splicing events pretreatment and posttreatment
compared to healthy controls [136]. Although this is the first
study using in-depth PD transcriptome sequencing, RNAseq
represents a promising technique to better study PD alterna-
tive splicing.
The role of miRNA and lncRNA in PD alternative
splicing modulation
A large number of alternative exon regions have been predict-
ed as binding sites of microRNAs (miRNAs). The latter is a
Neurogenetics
class of small noncoding RNA molecules, which mainly act as
posttranscriptional modulators of multiple target genes by par-
tial sequence complementarity. Through this mechanism, they
may also influence splicing process.
The interplay between miRNA differential expression
and alternative splicing modification in PD has been re-
cently investigated [137]. Parallel changes in miRNA pro-
files and their spliced targets have been observed in PD
leukocytes and PD-relevant brain regions (including the
substantia nigra as well as the frontal lobe). This study
was conducted through coupled analysis of small RNA
sequencing data, splice junction arrays, and exon arrays
[137].
Another novel fascinating class of RNAs with unknown
functions is long noncoding RNAs (lncRNAs), defined as
transcripts of over 200 nucleotides. The GENCODE non-
coding RNA set collects all lncRNAs known so far, in-
cluding several spliced transcript shorter than 200 bp.
LncRNA profiling has been recently assessed in PD leu-
kocytes predeep and postdeep brain stimulation via
RNAseq [136]. This survey allowed to identify some
lncRNAs overexpressed in PD and inversely decreased
following deep brain stimulation [136]. Differentially
expressed lncRNA includes the spliceosome component
U1, supporting the hypothesis of disease-involved splicing
modulations [136].
The identification of existing networks between noncoding
mRNAs and alternative splicing modifications represents an
important step forward the road to understanding the molecu-
lar basis of PD.
Conclusions
Alternative splicing is a highly harmonized process, based
on a combination of DNA sequence motifs, intronic and
exonic elements, regulatory factors, and temporal and spa-
tial signaling pathways. Mutations that disrupt any of these
critical features may alter the finely tuned splicing process-
es, upsetting the production or functions of the encoded
proteins, and finally causing human diseases. Assessing
the alternative splicing modulation of PD-related genes
represents an important point to understand PD molecular
etiology. Future studies, both with the standard or the new
currently available large-scale techniques, will offer a com-
plete data pool of the alternative splicing events in PD and
will provide new possible insights in order to develop strat-
egies for PD therapy and diagnosis.
Acknowledgments This study was supported by the international
Ph.D. program in Neuroscience of the University of Catania. We also
gratefully acknowledge Cristina Calì, Alfia Corsino, Maria Patrizia
D’Angelo, and Francesco Marino for their administrative and technical
support.
Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appro-
priate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
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