Figure - available from: Cellular and Molecular Neurobiology
This content is subject to copyright. Terms and conditions apply.
Lysosome-dependent degradation pathways; As indicated, a toxic α-synuclein aggregates are selectively degraded within the lysosome by means of LAMP-2A and chaperones; b GBA catalyzes the breakdown of sphingolipid glucosylceramide to ceramide and glucose within the lysosome; c damaged mitochondria is preferentially degraded by autophagosomal membrane engulfment and subsequent fusion with lysosome; d ATP13A2 is located inside the lysosomal membrane and its proper function is essential to the lysosomal membrane stability
Source publication
Parkinson disease (PD) is known as a common progressive neurodegenerative disease which is clinically diagnosed by the manifestation of numerous motor and nonmotor symptoms. PD is a genetically heterogeneous disorder with both familial and sporadic forms. To date, researches in the field of Parkinsonism have identified 23 genes or loci linked to ra...
Citations
... Gastro-retentive zinc cysteine tablet AD Ⅱ The orally administered active comparator material was associated with better tolerability, when compared to oral zinc acetate, and it induced a reduction in serum nonceruloplasmin bound copper levels, and an elevation in serum zinc levels Not researched HD AD: Alzheimer's disease; ALS: amyotrophic lateral sclerosis; MS: multiple sclerosis; PD: Parkinson's disease; HD: Huntington's disease pathology is characterized by the reduction of dopaminergic neurons, and the formation of protein aggregates that comprise of α-synuclein protofibrils [163] . Several genetic mutations of α-synuclein may exist in hereditary PD [164] . PD occurs in both inherited and sporadic forms. ...
The Author(s) 2024 [Abstract] Copper is an essential trace element, and plays a vital role in numerous physiological processes within the human body. During normal metabolism, the human body maintains copper homeostasis. Copper deficiency or excess can adversely affect cellular function. Therefore, copper homeostasis is stringently regulated. Recent studies suggest that copper can trigger a specific form of cell death, namely, cuproptosis, which is triggered by excessive levels of intracellular copper. Cuproptosis induces the aggregation of mitochondrial lipoylated proteins, and the loss of iron-sulfur cluster proteins. In neurodegenerative diseases, the pathogenesis and progression of neurological disorders are linked to copper homeostasis. This review summarizes the advances in copper homeostasis and cuproptosis in the nervous system and neurodegenerative diseases. This offers research perspectives that provide new insights into the targeted treatment of neurodegenerative diseases based on cuproptosis.
... Many PD patients also display gastrointestinal symptoms like constipation, which often precede motor symptoms, and an altered gut microbiome in comparison to healthy individuals. Gut microbiota is suggested to influence αsynuclein aggregation and motor deficits in mice, indicating a potential relationship between the gut microbiome and PD (46,47). The text discusses the Break hypothesis, which suggests that P PD may be initiated because of an immune system imbalance at nasal or intestinal mucosal sites. ...
Neurodegenerative diseases, including depression, Alzheimer's disease (AD), Parkinson's disease (PD) & multiple sclerosis (MS), pose significant challenges to global public health. It is characterized by the presence of neurotrophic plaques, cytokines, and chemokines in the central and peripheral nervous systems (CNS and PNS). The search for effective treatments has led to the investigation of natural compounds, and curcumin, a polyphenolic compound found in turmeric, has gained attention for its potential neuroprotective properties. It has long been utilized as a medical herb and culinary spice in Asian countries for a range of illnesses. This review centers on the latest developments and the underlying processes of curcumin's numerous natural benefits against neurodegenerative diseases, including Parkinson's disease. The current research indicates that the diagnosis of major depressive disorder (MDD) is related to both the neuroprotective benefits of antidepressants and cellular shrinkage and the death of neurons. The neuroprotection of curcumin against PD & AD is primarily attributed to its anti-inflammatory and antioxidant properties. In addition, according to reports curcumin improves striatal TH survival filaments additionally, pars compacta (SNPC) neurons, reduces aberrant turning geste, and exerts neuroprotective effects, at least partially, through a 7-nAChR-mediated medium. In multiple sclerosis (MS), an important part of the immune system is inflammation that leads to the damage seen in the CNS. Curcumin inhibits T cell, and IL-12 signaling and may be used to treat MS and other inflammatory conditions.
... Efforts to identify biomarkers of PD onset have been hampered by heterogeneity in clinical presentation and the rate of progression of patients 8 . Familial PD cases, both dominant and recessive, account for~10-15% of cases 9 , whilst the majority of remaining cases are considered idiopathic. The current largest GWAS meta-analysis identified 90 variants explaining~16-36% of PD heritability 10 , yet polygenic risk scoring is not currently at a stage to be used clinically to predict an individual's risk 10 . ...
Neurodegeneration in Parkinson’s disease (PD) precedes diagnosis by years. Early neurodegeneration may be reflected in RNA levels and measurable as a biomarker. Here, we present the largest quantification of whole blood linear and circular RNAs (circRNA) in early-stage idiopathic PD, using RNA sequencing data from two cohorts (PPMI = 259 PD, 161 Controls; ICICLE-PD = 48 PD, 48 Controls). We identified a replicable increase in TMEM252 and LMNB1 gene expression in PD. We identified novel differences in the expression of circRNAs from ESYT2 , BMS1P1 and CCDC9 , and replicated trends of previously reported circRNAs. Overall, using circRNA as a diagnostic biomarker in PD did not show any clear improvement over linear RNA, minimising its potential clinical utility. More interestingly, we observed a general reduction in circRNA expression in both PD cohorts, accompanied by an increase in RNASEL expression. This imbalance implicates the activation of an innate antiviral immune response and suggests a previously unknown aspect of circRNA regulation in PD.
... The disease pathology is characterized by the reduction of dopaminergic neurons, and the formation of protein aggregates that comprise of α-synuclein protofibrils [163] . Several genetic mutations of α-synuclein may exist in hereditary PD [164] . PD occurs in both inherited and sporadic forms. ...
Copper is an essential trace element, and plays a vital role in numerous physiological processes within the human body. During normal metabolism, the human body maintains copper homeostasis. Copper deficiency or excess can adversely affect cellular function. Therefore, copper homeostasis is stringently regulated. Recent studies suggest that copper can trigger a specific form of cell death, namely, cuproptosis, which is triggered by excessive levels of intracellular copper. Cuproptosis induces the aggregation of mitochondrial lipoylated proteins, and the loss of iron-sulfur cluster proteins. In neurodegenerative diseases, the pathogenesis and progression of neurological disorders are linked to copper homeostasis. This review summarizes the advances in copper homeostasis and cuproptosis in the nervous system and neurodegenerative diseases. This offers research perspectives that provide new insights into the targeted treatment of neurodegenerative diseases based on cuproptosis.
... Parkinson's disease is a complex neurodegenerative disorder with an increasingly intricate genetic background. While well-known monogenic forms with Mendelian inheritance exist, emerging evidence highlights the importance of oligogenic and polygenic effects, as well as the potential pathogenic role of endolysosomal or autophagosomal pathways and rare variants of genes in these pathways [1][2][3][4][5]. Pathogenic mutations of ß-glucocerebrosidase enzyme coding gene (GBA1) lead to Gaucher disease (GD) when inherited in the biallelic pattern. ...
Introduction
Parkinson’s disease (PD) has a complex genetic background involving both rare and common genetic variants. Although a small percentage of cases show a clear Mendelian inheritance pattern, it is much more relevant to identify patients who present with a complex genetic profile of risk variants with different severity. The ß-glucocerebrosidase coding gene ( GBA1 ) is recognized as the most frequent genetic risk factor for PD and Lewy body dementia, irrespective of reduction of the enzyme activity due to genetic variants.
Methods
In a selected cohort of 190 Hungarian patients with clinical signs of PD and suspected genetic risk, we performed the genetic testing of the GBA1 gene. As other genetic hits can modify clinical features, we also screened for additional rare variants in other neurodegenerative genes and assessed the APOE-ε genotype of the patients.
Results
In our cohort, we identified 29 GBA1 rare variant (RV) carriers. Out of the six different detected RVs, the highly debated E365K and T408M variants are composed of the majority of them (22 out of 32). Three patients carried two GBA1 variants, and an additional three patients carried rare variants in other neurodegenerative genes ( SMPD1 , SPG11 , and SNCA ). We did not observe differences in age at onset or other clinical features of the patients carrying two GBA1 variants or patients carrying heterozygous APOE-ε4 allele.
Conclusion
We need further studies to better understand the drivers of clinical differences in these patients, as this could have important therapeutic implications.
... The etiology of sporadic PD is complex and influenced by both environmental and genetic factors. Familial monogenic forms defined by rare and pathogenic variants in autosomal dominant (e.g., SNCA, LRRK2, VPS35) or recessive (PRKN, PINK1, PARK7) PD-related genes, account for less than 10% of Mendelian cases (Lesage and Brice, 2009;Karimi-Moghadam et al., 2018). The contribution of genetics in the remaining patients with sporadic forms of PD is not yet well defined. ...
Objectives
To explore the genetic architecture of PD in the Luxembourg Parkinson’s Study including cohorts of healthy people and patients with Parkinson’s disease (PD) and atypical parkinsonism (AP).
Methods
809 healthy controls, 680 PD and 103 AP were genotyped using the Neurochip array. We screened and validated rare single nucleotide variants (SNVs) and copy number variants (CNVs) within seven PD-causing genes ( LRRK2 , SNCA , VPS35 , PRKN , PARK7 , PINK1 and ATP13A2 ). Polygenic risk scores (PRSs) were generated using the latest genome-wide association study for PD. We then estimated the role of common variants in PD risk by applying gene-set-specific PRSs.
Results
We identified 60 rare SNVs in seven PD-causing genes, nine of which were pathogenic in LRRK2 , PINK1 and PRKN . Eleven rare CNVs were detected in PRKN including seven duplications and four deletions. The majority of PRKN SNVs and CNVs carriers were heterozygous and not differentially distributed between cases and controls. The PRSs were significantly associated with PD and identified specific molecular pathways related to protein metabolism and signal transduction as drivers of PD risk.
Conclusion
We performed a comprehensive genetic characterization of the deep-phenotyped individuals of the Luxembourgish Parkinson’s Study. Heterozygous SNVs and CNVs in PRKN were not associated with higher PD risk. In particular, we reported novel digenic variants in PD related genes and rare LRRK2 SNVs in AP patients. Our findings will help future studies to unravel the genetic complexity of PD.
... High levels of mitochondria DNA (mtDNA) deletions are reported to be associated with respiratory chain deficiency and selective neuronal loss in aging and PD [5][6][7][8][9]. Moreover, the identification of genes including PRKN, PINK1, DJ-1 and SNCA linked to familial variants of PD has revealed a common pathway involving mitochondrial quality control and dynamics [10][11][12][13]. All these have fueled research on the mitochondrial aspects of disease etiopathogenesis. ...
... Genetic studies focusing on monogenic forms of PD provided further support for the involvement of mitochondrial dysfunction in the disease. Pathogenic mutations in PINK1 (PARK6), PRKN (PARK2), DJ-1 (PARK7), SNCA (PARK1), FBXO7 (PARK15), CHCHD2 (PARK22) and VPS13C (PARK23) cause familial PD, and the majority of the proteins encoded are known to be involved in the mitochondrial quality control system and, in particular, mitophagy (Table 1) [13]. A recent study combining the availability of large-scale genome-wide association data in PD cases with current statistical tools, such as polygenic risk scoring and Mendelian randomization, further found potential causal association of 14 novel mitochondrial-function-associated genes with PD risk, and these genes are not only involved in mitophagy but implicate distinct mitochondrial processes [32]. ...
Mitochondrial dysregulation, such as mitochondrial complex I deficiency, increased oxidative stress, perturbation of mitochondrial dynamics and mitophagy, has long been implicated in the pathogenesis of PD. Initiating from the observation that mitochondrial toxins cause PD-like symptoms and mitochondrial DNA mutations are associated with increased risk of PD, many mutated genes linked to familial forms of PD, including PRKN, PINK1, DJ-1 and SNCA, have also been found to affect the mitochondrial features. Recent research has uncovered a much more complex involvement of mitochondria in PD. Disruption of mitochondrial quality control coupled with abnormal secretion of mitochondrial contents to dispose damaged organelles may play a role in the pathogenesis of PD. Furthermore, due to its bacterial ancestry, circulating mitochondrial DNAs can function as damage-associated molecular patterns eliciting inflammatory response. In this review, we summarize and discuss the connection between mitochondrial dysfunction and PD, highlighting the molecular triggers of the disease process, the intra- and extracellular roles of mitochondria in PD as well as the therapeutic potential of mitochondrial transplantation.
... The main finding emerging from this study is that 60% of the clinically diagnosed PD samples (76 out of 126) did not exhibit any variant in the genes we studied, thus suggesting that other genes may be involved. At the same time, the present study confirms the multifactorial pathophysiology of PD, where the genetic component is not always necessarily dominant in the development of the disease, and the role played by the complex interaction between environmental factors and genetic susceptibility [65,66]. ...
... In the review by Karimi-Moghadam et al. (2018) and by Day and Mullin (2021) [65,66], all major genes implicated in genetic subtypes, familial monogenic forms, and sporadic forms were listed. These included SNCA, PARKIN, UCHL1, PINK1, DJ-1, LRRK2, ATP13A2, GIGYF2, HTRA2, PLA2G6, VPS35, EIF4G1, DNAJC6, synaptojanin 1 (SYNJ1), DnaJ heat shock protein family (Hsp40) member C13 (DNAJC13), coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), vacuolar protein sorting 13 homolog C (VPS13C), GBA, spinocerebellar ataxia 2 (SCA2), transmembrane protein 230 (TMEM230), dynactin subunit 1 (DCTN1), and POLG. ...
... These included SNCA, PARKIN, UCHL1, PINK1, DJ-1, LRRK2, ATP13A2, GIGYF2, HTRA2, PLA2G6, VPS35, EIF4G1, DNAJC6, synaptojanin 1 (SYNJ1), DnaJ heat shock protein family (Hsp40) member C13 (DNAJC13), coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2), vacuolar protein sorting 13 homolog C (VPS13C), GBA, spinocerebellar ataxia 2 (SCA2), transmembrane protein 230 (TMEM230), dynactin subunit 1 (DCTN1), and POLG. However, despite several Whole-Genome Association Studies conducted on PD, heterogeneous results have been produced regarding the occurrence of genetic variants in these patients [65,66]. It is worth mentioning that all the aforementioned genes belong to the panel studied in this research using NGS, as shown in Table 1. ...
Parkinson’s disease (PD) is a multisystem and multifactorial disorder and, therefore, the application of modern genetic techniques may assist in unraveling its complex pathophysiology. We conducted a clinical–demographic evaluation of 126 patients with PD, all of whom were Caucasian and of Sicilian ancestry. DNA was extracted from the peripheral blood for each patient, followed by sequencing using a Next-Generation Sequencing system. This system was based on a custom gene panel comprising 162 genes. The sample underwent further filtering, taking into account the allele frequencies of genetic variants, their presence in the Human Gene Mutation Database, and their association in the literature with PD or other movement/neurodegenerative disorders. The largest number of variants was identified in the leucine-rich repeat kinase 2 (LRRK2) gene. However, variants in other genes, such as acid beta-glucosidase (GBA), DNA polymerase gamma catalytic subunit (POLG), and parkin RBR E3 ubiquitin protein ligase (PRKN), were also discovered. Interestingly, some of these variants had not been previously associated with PD. Enhancing our understanding of the genetic basis of PD and identifying new variants possibly linked to the disease will contribute to improved diagnostic accuracy, therapeutic developments, and prognostic insights for affected individuals.
... Although the low incidence of sporadic PD is extremely low, recent studies found that many of the genes in familial PD plays an essential role in mitochondrial function, such as α-synuclein (PARK1), UCHL1 (PARK5), LRRK2 (PARK8) dominant mutation, PINK1 (PARK6), DJ-1 (PARK7) mutations, and Parkin (PARK2) [7]. PD can be classifed into familial and sporadic types according to genetic pathogenesis, and gene mutations are more common in familial PD [8][9][10]. PINK1 genes are considered one of the common pathogenic genes that lead to autosomal recessive PD [11][12][13]. ...
Adenosine 5′-monophosphate-activated protein kinase (AMPK)’s effect in PTEN-induced kinase 1 (PINK1) mutant Parkinson’s disease (PD) transgenic flies and the related mechanism is seldom studied. The classic MHC-Gal4/UAS PD transgenic flies was utilized to generate the disease characteristics specifically expressed in flies’ muscles, and Western blot (WB) was used to measure the expression of the activated form of AMPK to investigate whether activated AMPK alters in PINK1B9 PD flies. MHC-Gal4 was used to drive AMPK overexpression in PINK1B9 flies to demonstrate the crucial role of AMPK in PD pathogenesis. The abnormal wing posture and climbing ability of PINK1B9 PD transgenic flies were recorded. Mitochondrial morphology via transmission electron microscopy (TEM) and ATP and NADH: ubiquinone oxidoreductase core subunit S3 (NDUFS3) protein levels were tested to evaluate the alteration of the mitochondrial function in PINK1B9 PD flies. Phosphorylated AMPKα dropped significantly in PINK1B9 flies compared to controls, and AMPK overexpression rescued PINKB9 flies’ abnormal wing posture rate. The elevated dopaminergic neuron number in PPL1 via immunofluorescent staining was observed. Mitochondrial dysfunction in PINK1B9 flies has been ameliorated with increased ATP level, restored mitochondrial morphology in muscle, and increased NDUFS3 protein expression. Conclusively, AMPK overexpression could partially rescue the PD flies via improving PINK1B9 flies’ mitochondrial function.
... In addition, familybased genetic studies have identified 23 genes that are associated with the development of PD; these genes exert differing functionalities, including deficiency of synaptic transmission, lysosomal dysfunction vesicular recycling, and mitophagy. Some of the genes involved include PARKIN, autosomal recessive juvenile parkinsonism, α-synuclein, inherited in an autosomal dominant, and PTEN-induced kinase (PINK1), and recessive early onset [21]. ...
