Figure 5 - uploaded by Uwe H. Leimer
Content may be subject to copyright.
![Synaptosomal localization of [A30P] ␣ SYN in transgenic mouse brain. Postnuclear supernatant from a 4-month-old male line 18 mouse was processed as described in Figure 2 A . The Western blot was sequentially probed with antiserum 3400 ( top panel ), Mc42 ( middle panel ), and anti- synaptophysin ( bottom panel ).](profile/Uwe-Leimer/publication/12357006/figure/fig4/AS:277286461952001@1443121652611/Synaptosomal-localization-of-A30P-SYN-in-transgenic-mouse-brain-Postnuclear.png)
Synaptosomal localization of [A30P] ␣ SYN in transgenic mouse brain. Postnuclear supernatant from a 4-month-old male line 18 mouse was processed as described in Figure 2 A . The Western blot was sequentially probed with antiserum 3400 ( top panel ), Mc42 ( middle panel ), and anti- synaptophysin ( bottom panel ).
Source publication
![Figure 4. Expression of [A30P] ␣ SYN in transgenic mouse brain. A ,...](profile/Uwe-Leimer/publication/12357006/figure/fig3/AS:277286461952000@1443121652574/Expression-of-A30P-SYN-in-transgenic-mouse-brain-A-Schematic-drawing-of-the_Q320.jpg)
![Figure 5. Synaptosomal localization of [A30P] ␣ SYN in transgenic mouse...](profile/Uwe-Leimer/publication/12357006/figure/fig4/AS:277286461952001@1443121652611/Synaptosomal-localization-of-A30P-SYN-in-transgenic-mouse-brain-Postnuclear_Q320.jpg)
Mutations in the alpha-synuclein (alphaSYN) gene are associated with rare cases of familial Parkinson's disease, and alphaSYN is a major component of Lewy bodies and Lewy neurites. Here we have investigated the localization of wild-type and mutant [A30P]alphaSYN as well as betaSYN at the cellular and subcellular level. Our direct comparative study...
Context in source publication
Context 1
... was suggested for [A30P]SYN. To prove this possibility in vivo, whole brain homog- enates of [A30P]SYN-expressing mice were subjected to the su- crose gradient floatation assay. Immunoblotting with the human- specific antibody 3400 revealed [A30P]SYN in both the highest density fraction 9 and the synaptophysin-containing floating frac- tions (Fig. 5). In the same animal, a very similar distribution was shown by Mc42, which detected both endogenous mouse SYN floatation assays were performed with postnuclear supernatant from rapidly pro- cessed temporal cortex gray matter of ep- ilepsy patients after lobotomy. Fractions were subjected to Tris-tricine-PAGE (4 - 20% gradient), and ...
Similar publications
Although misfolded and aggregated ?-synuclein (?-syn) is recognized in the disease progression of synucleinopathies, its role in the impairment of cortical circuitries and synaptic plasticity remains incompletely understood. We investigated how ?-synuclein accumulation affects synaptic plasticity in the mouse somatosensory cortex using two distinct...
Synucleinopathies are a broad class of neurodegenerative disorders characterized by the presence of intracellular protein aggregates containing α-synuclein protein. The aggregated α-synuclein protein is hyperphosphorylated on serine 129 (S129) compared to the unaggregated form of the protein. While the precise functional consequences of S129 hyperp...
There is extensive evidence in Parkinson's disease of a link between oxidative stress and some of the monogenically inherited Parkinson's disease-associated genes. This paper focuses on the importance of this link and potential impact on neuronal function. Basic mechanisms of oxidative stress, the cellular antioxidant machinery, and the main source...
Parkinson's disease is a common neurodegenerative disorder with the pathology of
α
-synuclein aggregation in Lewy bodies. Currently, there is no available therapy that arrests the progression of the disease. Therefore, the need of animal models to follow
α
-synuclein aggregation is crucial.
Drosophila melanogaster
has been researched extensively as...
Early α-synuclein (α-Syn)-induced alterations are neurite pathologies resulting in Lewy neurites. α-Syn oligomers are a toxic
species in synucleinopathies and are suspected to cause neuritic pathology. To investigate how α-Syn oligomers may be linked
to aberrant neurite pathology, we modeled different stages of α-Syn aggregation in vitro and invest...
Citations
... Cortical hyperexcitability has long been known to occur in murine models of AD (Palop et al., 2007). Previously in the same 2-4 months old human mutant α-syn expressing A30P mice (Kahle et al., 2000) used in the present study we reported spontaneous interictal discharges in vitro in the hippocampus following application of kainate to induce gamma frequency oscillations (Tweedy et al., 2021). This was never seen in slices from young wild type mice. ...
... Both male and female α-syn transgenic mice expressing human mutant α-syn (A30P) under the control of the Thy-1 promoter (Kahle et al., 2000) were used in this study. The A30P mice were bred in house from homozygous breeding pairs originally supplied by Dr. P Kahle, University of Tubingen. ...
... We have previously shown increased network excitability in the CA3 regions of the hippocampus in A30P mice at 2-4 months (Tweedy et al., 2021), several months prior to the onset of cognitive and motor dysfunction which occur at ∼12 and ∼14 months, respectively (Kahle et al., 2000;Freichel et al., 2007). To determine a possible role for neuroinflammation in the early network excitability changes, in the current study we have used mice aged either 1 month or 2-4 months, and first confirmed the expression of human α-syn in these two age groups ( Figure 1). ...
Introduction: Neuronal hyperexcitability and neuroinflammation are thought to occur at early stages in a range of neurodegenerative diseases. Neuroinflammation, notably activation of microglia, has been identified as a potential prodromal marker of dementia with Lewy bodies (DLB). Using a transgenic mouse model of DLB that over-expresses human mutant (A30P) alpha-synuclein (hα-syn) we have investigated whether early neuroinflammation is evident in the hippocampus in young pre-symptomatic animals.
Methods: Previous studies have shown early hyperexcitability in the hippocampal CA3 region in male A30P mice at 2–4 months of age, therefore, in the current study we have immunostained this region for markers of neuronal activity (c-Fos), reactive astrocytes (glial fibrillary acidic protein, GFAP), microglia (ionizing calcium binding adapter protein 1, Iba-1) and reactive microglia (inducible nitric oxide synthase, iNOS).
Results: We found an interesting biphasic change in the expression of c-Fos in A30P mice with high expression at 1 month, consistent with early onset of hyperexcitability, but lower expression from 2–4 months in male A30P mice compared to wild-type (WT) controls, possibly indicating chronic hyperexcitability. Neuroinflammation was indicated by significant increases in the % area of GFAP and the number of Iba-1+ cells that expressed iNOS immunoreactivity in the CA3 region in 2–4 months A30P male mice compared to WT controls. A similar increase in % area of GFAP was observed in female A30P mice, however, the Iba-1 count was not different between female WT and A30P mice. In WT mice aged 2–4 months only 4.6% of Iba-1+ cells co-expressed iNOS. In contrast, in age matched A30P mice 87% of cells co-expressed Iba-1 and iNOS. Although there was no difference in GFAP immunoreactivity at 1 month, Iba-1/iNOS co-expression was also increased in a cohort of 1 month old A30P mice.
Discussion: Abnormal hα-syn expression in A30P mice caused early changes in network excitability, as indicated by c-Fos expression, and neuroinflammation which might contribute to disease progression.
... These membrane trafficking mechanisms have received considerable attention owing to their potential roles as initiators or enhancers of the neurodegenerative processes leading to LBD [30]. α-Syn is a membrane-binding protein with a number of possible normal functions including control of synaptic membrane processes and biogenesis, regulation of neurotransmitter release, and synaptic plasticity [31][32][33][34][35][36]. However, overexpression of wild-type and mutated α-syn [35,37], oligomeric α-syn [34], and small (less than 200 nm) non-fibrillar α-syn [38] can cause loss of membrane integrity, thinning the membrane and/or the formation of pores in the cell membrane, leading to uncontrolled diffusion of molecules in and out of the cell [35]. ...
Lewy body diseases (LBDs) feature α-synuclein (α-syn)-containing Lewy bodies, with misfolded α-syn potentially propagating as seeds. Using a seeding amplification assay, we previously reported distinct α-syn seeding in LBD cases based on the area under seeding curves. This study revealed that LBD cases showing different α-syn seeding kinetics have distinct proteomics profiles, emphasizing disruptions in mitochondria and lipid metabolism in high-seeder cases. Though the mechanisms underlying LBD development are intricate, the factors influencing α-syn seeding activity remain elusive. To address this and complement our previous findings, we conducted targeted transcriptome analyses in the substantia nigra using the nanoString nCounter assay together with histopathological evaluations in high (n = 4) and low (n = 3) nigral α-syn seeders. Neuropathological findings (particularly the substantia nigra) were consistent between these groups and were characterized by neocortical LBD associated with Alzheimer’s disease neuropathologic change. Among the 1811 genes assessed, we identified the top 20 upregulated and downregulated genes and pathways in α-syn high seeders compared with low seeders. Notably, alterations were observed in genes and pathways related to transmembrane transporters, lipid metabolism, and the ubiquitin–proteasome system in the high α-syn seeders. In conclusion, our findings suggest that the molecular behavior of α-syn is the driving force in the neurodegenerative process affecting the substantia nigra through these identified pathways. These insights highlight their potential as therapeutic targets for attenuating LBD progression.
... However, the impact of αSyn pathology on the integrity of the midbrain DA system remains to be uncovered [38][39][40][41][42][43]. Further, while PD patients suffer from synucleinopathy and DA cell loss, it is still debated if mouse models of synucleinopathy show DA cell pathology relevant to PD [39,40,[42][43][44][45][46]. ...
... Several different animal models have been used for investigating pathological and mechanistic aspects of PD with varying degrees of similarity to PD and representing a varying range of symptom domains. In literature, some, but not all, mice models aiming to mimic αSyn-induced pathology give rise to PD-like symptoms [40,42,46,71,76]. The two transgenic mouse lines addressed here have been verified to show αSyn pathology. ...
Aim: Parkinson’s disease (PD) is characterized by degeneration of midbrain dopamine neurons and synucleinopathy [aggregated alpha-synuclein protein (αSyn)]. The correlation between αSyn pathology and dopamine neuron degeneration remains to be fully established. Mouse models of PD are commonly used to increase knowledge of disease mechanisms. Lately, midbrain dopamine neurons have gained attention as more heterogeneous than previously recognized. With the aim to determine how the midbrain dopamine system in mice is affected in the presence of αSyn pathology, this brain system was studied in two transgenic mouse models of synucleinopathy. Methods: Brain sections from two previously described transgenic mouse lines verified for αSyn pathology through expression of the human αSyn gene (SNCA) under control of the Thy-1 promoter [Thy1-h[A30P]αSyn and Thy1-h[wt]αSyn (L61)], were analyzed using fluorescent in situ hybridization (FISH) and compared with matching sections from wild-type control mice. Probes directed towards mouse and human αSyn mRNA, and a battery of probes towards mRNAs representative of dopamine cell identity and heterogeneity, were implemented. Results: First, validation of αSyn-encoding mRNA was performed. Ample ectopic αSyn mRNA was observed throughout the brain of mice of each transgenic line. Next, midbrain dopamine neurons located in substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were analyzed using a battery of general and subpopulation-specific dopamine cell markers. This included tyrosine hydroxylase (Th), vesicular monoamine transporter 2 (Vmat2), dopamine transporter (Dat), aldehyde dehydrogenase 1 family member A1 (Aldh1a1), G-protein-activated inward-rectifying potassium channel type 2 (Girk2), calbindin 1 (Calb1), Calb2, gastrin-releasing peptide (Grp), and vesicular glutamate transporter 2 (Vglut2) mRNAs. No difference between transgenic and control mice was observed for any analyzed marker in either the Thy1-h[A30P]αSyn or Thy1-h[wt]αSyn transgenic mouse line. Conclusions: This study demonstrates remarkable robustness of midbrain dopamine cell integrity in the presence of brain-wide ectopic human αSyn in two transgenic mouse models of neurodegenerative disease, motivating further study into mechanisms correlating synucleinopathy with dopamine neuron degeneration in rodent models relevant to PD.
... αSyn is an intracellular protein of 140 amino acid residues predominantly expressed in presynaptic terminals throughout the central nervous system. Although the physiological role of αSyn remains unclear, it may regulate synaptic activity such as neurotransmitter release and synaptic plasticity [4][5][6]. Abnormal accumulation of αSyn, especially the oligomeric αSyn, in axons and presynaptic terminals promotes the degeneration of dopaminergic neurons [7][8][9]. The formation of αSyn oligomers is affected by modulating the synthesis, aggregation, or degradation of αSyn [10,11]. ...
Abnormal accumulation of alpha-synuclein (αSyn) in the remaining nigra dopaminergic neurons is a common neuropathological feature found in patients with Parkinson’s disease (PD). Antibody-based immunotherapy has been considered a potential approach for PD treatment. This study aims to investigate the effectiveness of active immunization against αSyn in a mouse model of PD. Adult mice were immunized with or without a synthetic peptide containing the C-terminal residues of human αSyn and activation epitopes, followed by an intranigral injection of adeno-associated virus vectors for overexpressing human αSyn. Upon the peptide injection, αSyn-specific antibodies were raised, accompanied by degeneration of dopaminergic neurons and motor deficits. Furthermore, the induction of neuroinflammation was postulated by the elevation of astroglial and microglial markers in the immunized mice. Instead of lessening αSyn toxicity, this peptide vaccine caused an increase in the pathogenic species of αSyn. Our data demonstrated the potential adverse effects of active immunization to raise antibodies against the C-terminal fragment of αSyn. This drawback highlights the need for further investigation to weigh the pros and cons of immunotherapy in PD. Applying the αSyn C-terminal peptide vaccine for PD treatment should be cautiously exercised. This study provides valuable insights into the intricate interplay among immune intervention, αSyn accumulation, and neurodegeneration.
... In Parkinson's disease, αS is the primary component of intracellular fibrillar aggregates that are the hallmark of disease Galvin et al., 1999). Natively, αS is primarily localized to presynaptic termini (Maroteaux et al., 1988;Kahle et al., 2000), where it binds reversibly to cellular membranes (Kahle et al., 2000;Bussell and Eliezer, 2003;Fortin et al., 2004;Bendor et al., 2013). Because of its central role in Parkinson's disease and other synucleinopathies, αS is of major biomedical interest. ...
... In Parkinson's disease, αS is the primary component of intracellular fibrillar aggregates that are the hallmark of disease Galvin et al., 1999). Natively, αS is primarily localized to presynaptic termini (Maroteaux et al., 1988;Kahle et al., 2000), where it binds reversibly to cellular membranes (Kahle et al., 2000;Bussell and Eliezer, 2003;Fortin et al., 2004;Bendor et al., 2013). Because of its central role in Parkinson's disease and other synucleinopathies, αS is of major biomedical interest. ...
The aggregation of the disordered neuronal protein, α-Synuclein (αS), is the primary pathological feature of Parkinson's disease. Current hypotheses favor cell-to-cell spread of αS species as underlying disease progression, driving interest in identifying the molecular species and cellular processes involved in cellular internalization of αS. Prior work from our lab identified the chemically specific interaction between αS and the pre-synaptic adhesion protein neurexin 1β (N1β) to be capable of driving cellular internalization of both monomer and aggregated forms of αS. Here we explore the physical basis of N1β-driven internalization of αS. Specifically, we show that spontaneous internalization of αS by SH-SY5Y and HEK293 cells expressing N1β requires essentially all of the membrane-binding domain of αS; αS constructs truncated beyond residue 90 bind to N1β in the plasma membrane of HEK cells, but are not internalized. Interestingly, prior to internalization, αS and N1β co-diffuse rapidly in the plasma membrane. αS constructs that are not internalized show very slow mobility themselves, as well as slow N1β diffusion. Finally, we find that truncated αS is capable of blocking internalization of full-length αS. Our results draw attention to the potential therapeutic value of blocking αS-N1β interactions.
... These inclusions were associated with decreased striatal dopamine and with motor deficits at~12 months [18]. However, other studies expressing WT or mutant α-syn under the control of different promoters (Thy-1 and tyrosine hydroxylase), despite showing inclusions, fail to reproduce the motor phenotype or dopaminergic deficits [19,20]. Therefore, although the events that lead to the assembly of soluble α-syn into insoluble filamentous assemblies constitute the seminal pathological event in these diseases, additional factors in α-syn aggregation may be required for the development of disease. ...
Alpha-synucleinopathies (α-synucleinopathies) such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are all characterized by aggregates of alpha-synuclein (α-syn), but display heterogeneous clinical and pathological phenotypes. The mechanism underlying this heterogeneity is thought to be due to diversity in the α-syn strains present across the diseases. α-syn obtained from the post-mortem brain of patients who lived with these conditions is heterogenous, and displays a different protease sensitivity, ultrastructure, cytotoxicity, and seeding potential. The primary aim of this review is to summarize previous studies investigating these concepts, which not only reflect the idea of different syn strains being present, but demonstrate that each property explains a small part of a much larger puzzle. Strains of α-syn appear at the center of the correlation between α-syn properties and the disease phenotype, likely influenced by external factors. There are considerable similarities in the properties of disease-specific α-syn strains, but MSA seems to consistently display more aggressive traits. Elucidating the molecular underpinnings of heterogeneity amongst α-synucleinopathies holds promise for future clinical translation, allowing for the development of personalized medicine approaches tackling the root cause of each α-synucleinopathy.
... The dominantly inherited A30P and A53T mutations are believed to be pathogenic by promoting self-oligomerization of α-syn [11]. The (Thy-1)-h[A30P] α-syn transgenic (tg) mouse model overexpresses human A30P α-syn under the Thy-1 promoter and features aggregated α-syn accumulation in neuronal cell bodies and neurites [12,13]. Further, these mice display early behavioral disturbances, such as memory impairment, as well as late-life motor symptoms, including paralysis and impaired coordination with a variable age of onset [14,15]. ...
... α-syn tg mice [12], expressing human α-syn with the A30P mutation under the Thy-1 promoter, were used for the study. All animals were housed at the National Veterinary Institute (Uppsala, Sweden) in open cages on a 12:12 h reversed dark: light cycle, with food and water available ad libitum. ...
Immunotherapy against alpha-synuclein (α-syn) is a promising novel treatment strategy for Parkinson's disease (PD) and related α-synucleinopathies. We have previously shown that systemic treatment with the monoclonal oligomer/protofibril-selective antibody mAb47 targeting cytotoxic α-syn leads to reduced central nervous system levels of such species as well as an indication of reduced late-stage symptoms in aged (Thy-1)-h[A30P] α-syn transgenic mice. Here, we performed an early-onset long-term treatment study with this antibody to evaluate effects on brain pathology and behavioral outcomes in the same mouse model. Compared to the placebo group, the treatment strongly reduced phosphorylated α-syn (pS129 α-syn) pathology in the upper brain stem. Moreover, a preserved recognition memory and risk assessment behavior could be seen in antibody-treated mice at six months of age, even although these effects were no longer significant at eleven months of age. Importantly, no evidence of inflammatory responses or other potential toxic effects was seen with the treatment. Taken together, this study supports the strategy to target α-syn oligomers/protofibrils with monoclonal antibodies to counteract early symptoms and slow down the progression of PD and other α-synucleinopathies.
... In Parkinson's disease, αS is the primary component of intracellular fibrillar aggregates that are the hallmark of disease (Galvin et al., 1999;Spillantini et al., 1998). Natively, αS is primarily localized to pre-synaptic termini (Kahle et al., 2000;Maroteaux et al., 1988), where it binds reversibly to cellular membranes (Bendor et al., 2013;Bussell and Eliezer, 2003;Fortin et al., 2004;Kahle et al., 2000). Because of its central role in Parkinson's disease and other synucleinopathies, αS is of major biomedical interest. ...
... In Parkinson's disease, αS is the primary component of intracellular fibrillar aggregates that are the hallmark of disease (Galvin et al., 1999;Spillantini et al., 1998). Natively, αS is primarily localized to pre-synaptic termini (Kahle et al., 2000;Maroteaux et al., 1988), where it binds reversibly to cellular membranes (Bendor et al., 2013;Bussell and Eliezer, 2003;Fortin et al., 2004;Kahle et al., 2000). Because of its central role in Parkinson's disease and other synucleinopathies, αS is of major biomedical interest. ...
The aggregation of the disordered neuronal protein, α-Synuclein (αS), is the primary pathological feature of Parkinson’s disease. Current hypotheses favor cell-to-cell spread of αS species as underlying disease progression, driving interest in identifying the molecular and cellular species involved in cellular internalization of αS. Prior work from our lab identified the chemically specific interaction between αS and the pre-synaptic adhesion protein neurexin 1β (N1β) to be capable of driving cellular internalization of both monomer and aggregated forms of αS. Here we explore the physical basis of N1β-driven internalization of αS. Specifically, we show that spontaneous internalization of αS by SH-SY5Y and HEK293 cells expressing N1β requires essentially all of the membrane-binding domain of αS; αS constructs truncated beyond residue 90 bind to N1β in the plasma membrane of HEK cells, but are not internalized. Interestingly, prior to internalization, αS and N1β co-diffuse rapidly in the plasma membrane. αS constructs that are not internalized show very slow mobility themselves, as well as slow N1β diffusion. Finally, we find that truncated αS is capable of blocking internalization of full-length αS. Our results draw attention to the potential therapeutic value of blocking αS-N1β interactions.
... For the described experiments homozygous (Thy-1)-h[A30P]-αsynuclein mice (refs. 47,99 ; kindly donated by Philipp Kahle) extensively backcrossed (>10 generations) into C57Bl6/J background were used. Phenotype development in this transgenic model is dose dependent with earlier onset of pathology in homozygous compared to heterozygous animals. ...
Prion-like transmission of pathology in α-synucleinopathies like Parkinson’s disease or multiple system atrophy is increasingly recognized as one potential mechanism to address disease progression. Active and passive immunotherapies targeting insoluble, aggregated α-synuclein are already being actively explored in the clinic with mixed outcomes so far. Here, we report the identification of 306C7B3, a highly selective, aggregate-specific α-synuclein antibody with picomolar affinity devoid of binding to the monomeric, physiologic protein. 306C7B3 binding is Ser129-phosphorylation independent and shows high affinity to several different aggregated α-synuclein polymorphs, increasing the likelihood that it can also bind to the pathological seeds assumed to drive disease progression in patients. In support of this, highly selective binding to pathological aggregates in postmortem brains of MSA patients was demonstrated, with no staining in samples from other human neurodegenerative diseases. To achieve CNS exposure of 306C7B3, an adeno-associated virus (AAV) based approach driving expression of the secreted antibody within the brain of (Thy-1)-[A30P]-hα-synuclein mice was used. Widespread central transduction after intrastriatal inoculation was ensured by using the AAV2HBKO serotype, with transduction being spread to areas far away from the inoculation site. Treatment of (Thy-1)-[A30P]-hα-synuclein mice at the age of 12 months demonstrated significantly increased survival, with 306C7B3 concentration reaching 3.9 nM in the cerebrospinal fluid. These results suggest that AAV-mediated expression of 306C7B3, targeting extracellular, presumably disease-propagating aggregates of α-synuclein, has great potential as a disease-modifying therapy for α-synucleinopathies as it ensures CNS exposure of the antibody, thereby mitigating the selective permeability of the blood-brain barrier.
... These structural and biophysical properties probably hold the key to their normal and abnormal function [91,92]. α-Syn is abundantly expressed in all neuronal types, where it localizes in presynaptic terminals [93][94][95] and modulates synaptic functions [96][97][98]. However, α-Syn is among the last presynaptic proteins to become enriched at the synapse [94] and unlike γ-Syn, it does not seem to be involved in synaptic development [99,100]. ...
In patients affected by Parkinson’s disease (PD), up to 50% of them experience cognitive changes, and psychiatric disturbances, such as anxiety and depression, often precede the onset of motor symptoms and have a negative impact on their quality of life. Pathologically, PD is characterized by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of intracellular inclusions, called Lewy bodies and Lewy neurites, composed mostly of α-synuclein (α-Syn). Much of PD research has focused on the role of α-Syn aggregates in the degeneration of SNc DA neurons due to the impact of striatal DA deficits on classical motor phenotypes. However, abundant Lewy pathology is also found in other brain regions including the midbrain raphe nuclei, which may contribute to non-motor symptoms. Indeed, dysfunction of the serotonergic (5-HT) system, which regulates mood and emotional pathways, occurs during the premotor phase of PD. However, little is known about the functional consequences of α-Syn inclusions in this neuronal population other than DA neurons. Here, we provide an overview of the current knowledge of α-Syn and its role in regulating the 5-HT function in health and disease. Understanding the relative contributions to α-Syn-linked alterations in the 5-HT system may provide a basis for identifying PD patients at risk for developing depression and could lead to a more targeted therapeutic approach.
