SNCA Mutations Research Articles

Olfactory deficit and gastrointestinal dysfunction precede motor abnormalities in alpha-Synuclein G51D knock-in mice

Parkinson's disease (PD) is typically a sporadic late-onset disorder, which has made it difficult to model in mice. Several transgenic mouse models bearing mutations in SNCA, which encodes alpha-Synuclein (α-Syn), have been made, but these lines do not express SNCA in a physiologically accurate spatiotemporal pattern, which limits the ability of the mice to recapitulate the features of human PD. Here, we generated knock-in mice bearing the G51D SNCA mutation. After establishing that their motor symptoms begin at 9 mo of age, we then sought earlier pathologies. We assessed the phosphorylation at Serine 129 of α-Syn in different tissues and detected phospho-α-Syn in the olfactory bulb and enteric nervous system at 3 mo of age. Olfactory deficit and impaired gut transit followed at 6 mo, preceding motor symptoms. The SncaG51D mice thus parallel the progression of human PD and will enable us to study PD pathogenesis and test future therapies.

The First East Asian Patient With Parkinson's Disease Caused by the A53E SNCA Mutation With Early Progression to Dementia.

The First East Asian Patient With Parkinson's Disease Caused by the A53E SNCA Mutation With Early Progression to Dementia.

Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson’s patients

Synucleinopathies such as Parkinson’s disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Recent Advances in Understanding and Treating Parkinson’s Disease

Tremor, bradykinesia, rigidity, and postural instability are some of the motor symptoms that are associated with Parkinson's disease (PD), which is a neurodegenerative ailment that is becoming increasingly common. This review provides a summary of current developments in Parkinson's disease (PD) research, with a particular emphasis on the disease's pathophysiology, diagnostic tools, and treatment possibilities. Alpha-synuclein aggregation into Lewy bodies is a defining pathogenic feature of Parkinson's disease (PD), which is primarily caused by the gradual death of dopaminergic neurones in the substantia nigra. Although idiopathic Parkinson's disease accounts for the vast majority of cases, familial variants of the condition are caused by genetic mutations in SNCA, LRRK2, PARK7, PINK1, and PRKN. These mutations provide insights into the molecular pathways that underlie the disease. Improved imaging techniques, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), as well as the investigation of cerebrospinal fluid (CSF) and blood-based biomarkers, are examples of the diagnostic breakthroughs that have been made. Therapeutic techniques have developed over time, with pharmacological treatments such as levodopa and dopamine agonists playing significant roles. These treatments are supplemented by non-pharmacological options such as deep brain stimulation (DBS). Recent advances in medicine, such as gene therapy and stem cell therapy, have the potential to bring about further advances in the future. In this review, the most important findings are summarised, trends are identified, and the implications of recent research for the management of Parkinson's disease are discussed respectively.

Dopamine‑iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease

Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson's disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the α-synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment resulted in increased expression of the transmembrane iron transporters transferrin receptor 1 (TFR1), ferroportin (FPN), and mitoferrin2 (MFRN2) and intracellular iron accumulation, suggesting that dopamine may promote iron uptake. Furthermore, dopamine supplementation led to reduced mitochondrial fitness including decreased mitochondrial respiration, increased cytochrome c control efficiency, reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenous SNCA mutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore the disturbed regulatory network in PD cells.

Resequencing the complete SNCA locus in Indian patients with Parkinson’s disease

The genetic loci implicated in familial Parkinson’s disease (PD) have limited generalizability to the Indian PD population. We tested mutations and the frequency of known mutations in the SNCA gene in a PD cohort from India. We selected 298 PD cases and 301 age-matched controls for targeted resequencing (before QC), along with 363 PD genomes of Indian ancestry and 1029 publicly available whole genomes from India as healthy controls (IndiGenomes), to determine the frequency of monogenic SNCA mutations. The raw sequence reads were analyzed using an in-house analysis pipeline, allowing the detection of small variants and structural variants using Manta. The in-depth analysis of the SNCA locus did not identify missense or structural variants, including previously identified SNCA mutations, in the Indian population. The familial forms of SNCA gene variants do not play a major role in the Indian PD population and this warrants further research in the under-represented population.

Assessment of Mitochondrial Gene Activity in Dopaminergic Neuron Cultures Derived from Induced Pluripotent Stem Cells Obtained from Parkinson's Disease Patients

Introduction. Induced pluripotent stem cells (iPSCs) culturing allows modelling of neurodegenerative diseases in vitro and discovering its early biomarkers.
 Our objective was to evaluate the activity of genes involved in mitochondrial dynamics and functions in genetic forms of Parkinson's disease (PD) using cultures of dopaminergic neurons derived from iPSCs.
 Materials and methods. Dopaminergic neuron cultures were derived by reprogramming of the cells obtained from PD patients with SNCA and LRRK2 gene mutations, as well as from a healthy donor for control. Expression levels of 112 genes regulating mitochondrial structure, dynamics, and functions were assessed by multiplex gene expression profiling using NanoString nCounter custom mitochondrial gene expression panel.
 Results. When comparing the characteristics of the neurons from patients with genetic forms of PD to those of the control, we observed variations in the gene activity associated with the mitochondrial respiratory chain, the tricarboxylic acid cycle enzyme activities, biosynthesis of amino acids, oxidation of fatty acids, steroid metabolism, calcium homeostasis, and free radical quenching. Several genes in the cell cultures with SNCA and LRRK2 gene mutations exhibited differential expression. Moreover, these genes regulate mitophagy, mitochondrial DNA synthesis, redox reactions, cellular detoxification, apoptosis, as well as metabolism of proteins and nucleotides.
 Conclusions. The changes in gene network expression found in this pilot study confirm the role of disrupted mitochondrial homeostasis in the molecular pathogenesis of PD. These findings may contribute to the development of biomarkers and to the search for new therapeutic targets for the treatment of SNCA- and LRRK2-associated forms of the disease.

Analysis of α-syn and parkin interaction in mediating neuronal death in Drosophila model of Parkinson's disease.

One of the hallmarks of Parkinson's Disease (PD) is aggregation of incorrectly folded α-synuclein (SNCA) protein resulting in selective death of dopaminergic neurons. Another form of PD is characterized by the loss-of-function of an E3-ubiquitin ligase, parkin. Mutations in SNCA and parkin result in impaired mitochondrial morphology, causing loss of dopaminergic neurons. Despite extensive research on the individual effects of SNCA and parkin, their interactions in dopaminergic neurons remain understudied. Here we employ Drosophila model to study the effect of collective overexpression of SNCA along with the downregulation of parkin in the dopaminergic neurons of the posterior brain. We found that overexpression of SNCA along with downregulation of parkin causes a reduction in the number of dopaminergic neuronal clusters in the posterior region of the adult brain, which is manifested as progressive locomotor dysfunction. Overexpression of SNCA and downregulation of parkin collectively results in altered mitochondrial morphology in a cluster-specific manner, only in a subset of dopaminergic neurons of the brain. Further, we found that SNCA overexpression causes transcriptional downregulation of parkin. However, this downregulation is not further enhanced upon collective SNCA overexpression and parkin downregulation. This suggests that the interactions of SNCA and parkin may not be additive. Our study thus provides insights into a potential link between α-synuclein and parkin interactions. These interactions result in altered mitochondrial morphology in a cluster-specific manner for dopaminergic neurons over a time, thus unraveling the molecular interactions involved in the etiology of Parkinson's Disease.

In vivo18F-DOPA PET imaging identifies a dopaminergic deficit in a rat model with a G51D α-synuclein mutation.

Parkinson's disease (PD) is a neurodegenerative condition with several major hallmarks, including loss of substantia nigra neurons, reduction in striatal dopaminergic function, and formation of α-synuclein-rich Lewy bodies. Mutations in SNCA, encoding for α-synuclein, are a known cause of familial PD, and the G51D mutation causes a particularly aggressive form of the condition. CRISPR/Cas9 technology was used to introduce the G51D mutation into the endogenous rat SNCA gene. SNCAG51D/+ and SNCAG51D/G51D rats were born in Mendelian ratios and did not exhibit any severe behavourial defects. L-3,4-dihydroxy-6-18F-fluorophenylalanine (18F-DOPA) positron emission tomography (PET) imaging was used to investigate this novel rat model. Wild-type (WT), SNCAG51D/+ and SNCAG51D/G51D rats were characterized over the course of ageing (5, 11, and 16 months old) using 18F-DOPA PET imaging and kinetic modelling. We measured the influx rate constant (Ki) and effective distribution volume ratio (EDVR) of 18F-DOPA in the striatum relative to the cerebellum in WT, SNCAG51D/+ and SNCAG51D/G51D rats. A significant reduction in EDVR was observed in SNCAG51D/G51D rats at 16 months of age indicative of increased dopamine turnover. Furthermore, we observed a significant asymmetry in EDVR between the left and right striatum in aged SNCAG51D/G51D rats. The increased and asymmetric dopamine turnover observed in the striatum of aged SNCAG51D/G51D rats reflects one aspect of prodromal PD, and suggests the presence of compensatory mechanisms. SNCAG51D rats represent a novel genetic model of PD, and kinetic modelling of 18F-DOPA PET data has identified a highly relevant early disease phenotype.

Sporadic SNCA mutations A18T and A29S exhibit variable effects on protein aggregation, cell viability and oxidative stress.

α-synuclein aggregation is the hallmark feature of Parkinson's disease. Both familial and sporadic forms of the disease exhibit this feature. Several mutations have been identified in patients and are associated with the disease pathology. We have used site-directed mutagenesis to generate α-synuclein mutant variants tagged with GFP. Fluorescence microscopy, flow cytometry, western blotting, cell viability and oxidative stress analysis were performed to investigate the effect of two less studied α-synuclein variants. In this study we characterized two less studied α-synuclein mutations, A18T and A29S, in the well-established yeast model. Our data shows variable expression, distribution and toxicity of the protein in the mutant variants A18T, A29S, A53T and WT. The cells expressing the double mutant variant A18T/A53T showed the most increase in the aggregation phenotype and also depicted reduced viability suggesting a more substantial effect of this variant. The outcome of our study highlights the variable localization, aggregation phenotype and toxicity of the studied α-synuclein variants. This underscores the importance of in-depth analysis of every disease-associated mutation which may result in variable cellular phenotype.

The G51D SNCA mutation generates a slowly progressive α-synuclein strain in early-onset Parkinson’s disease

Unique strains of α-synuclein aggregates have been postulated to underlie the spectrum of clinical and pathological presentations seen across the synucleinopathies. Whereas multiple system atrophy (MSA) is associated with a predominance of oligodendroglial α-synuclein inclusions, α-synuclein aggregates in Parkinson’s disease (PD) preferentially accumulate in neurons. The G51D mutation in the SNCA gene encoding α-synuclein causes an aggressive, early-onset form of PD that exhibits clinical and neuropathological traits reminiscent of both PD and MSA. To assess the strain characteristics of G51D PD α-synuclein aggregates, we performed propagation studies in M83 transgenic mice by intracerebrally inoculating patient brain extracts. The properties of the induced α-synuclein aggregates in the brains of injected mice were examined using immunohistochemistry, a conformational stability assay, and by performing α-synuclein seed amplification assays. Unlike MSA-injected mice, which developed a progressive motor phenotype, G51D PD-inoculated animals remained free of overt neurological illness for up to 18 months post-inoculation. However, a subclinical synucleinopathy was present in G51D PD-inoculated mice, characterized by the accumulation of α-synuclein aggregates in restricted regions of the brain. The induced α-synuclein aggregates in G51D PD-injected mice exhibited distinct properties in a seed amplification assay and were much more stable than those present in mice injected with MSA extract, which mirrored the differences observed between human MSA and G51D PD brain samples. These results suggest that the G51D SNCA mutation specifies the formation of a slowly propagating α-synuclein strain that more closely resembles α-synuclein aggregates associated with PD than MSA.

New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy

A 21-nucleotide duplication in one allele of SNCA was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion of MAAAEKT after residue 22 of α-synuclein, resulting in a protein of 147 amino acids. Both wild-type and mutant proteins were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new α-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36–100 of wild-type α-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA Type I and Type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. In vitro assembly of recombinant wild-type α-synuclein, its insertion mutant and their mixture yielded structures that were distinct from those of JOS filaments. Our findings provide insight into a possible mechanism of JOS fibrillation in which mutant α-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation.

Protein aggregation and calcium dysregulation are hallmarks of familial Parkinson’s disease in midbrain dopaminergic neurons

Mutations in the SNCA gene cause autosomal dominant Parkinson’s disease (PD), with loss of dopaminergic neurons in the substantia nigra, and aggregation of α-synuclein. The sequence of molecular events that proceed from an SNCA mutation during development, to end-stage pathology is unknown. Utilising human-induced pluripotent stem cells (hiPSCs), we resolved the temporal sequence of SNCA-induced pathophysiological events in order to discover early, and likely causative, events. Our small molecule-based protocol generates highly enriched midbrain dopaminergic (mDA) neurons: molecular identity was confirmed using single-cell RNA sequencing and proteomics, and functional identity was established through dopamine synthesis, and measures of electrophysiological activity. At the earliest stage of differentiation, prior to maturation to mDA neurons, we demonstrate the formation of small β-sheet-rich oligomeric aggregates, in SNCA-mutant cultures. Aggregation persists and progresses, ultimately resulting in the accumulation of phosphorylated α-synuclein aggregates. Impaired intracellular calcium signalling, increased basal calcium, and impairments in mitochondrial calcium handling occurred early at day 34–41 post differentiation. Once midbrain identity fully developed, at day 48–62 post differentiation, SNCA-mutant neurons exhibited mitochondrial dysfunction, oxidative stress, lysosomal swelling and increased autophagy. Ultimately these multiple cellular stresses lead to abnormal excitability, altered neuronal activity, and cell death. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease.

High-content phenotyping of Parkinson's disease patient stem cell-derived midbrain dopaminergic neurons using machine learning classification.

SummaryCombining multiple Parkinson's disease (PD) relevant cellular phenotypes might increase the accuracy of midbrain dopaminergic neuron (mDAN) in vitro models. We differentiated patient-derived induced pluripotent stem cells (iPSCs) with a LRRK2 G2019S mutation, isogenic control, and genetically unrelated iPSCs into mDANs. Using automated fluorescence microscopy in 384-well-plate format, we identified elevated levels of α-synuclein (αSyn) and serine 129 phosphorylation, reduced dendritic complexity, and mitochondrial dysfunction. Next, we measured additional image-based phenotypes and used machine learning (ML) to accurately classify mDANs according to their genotype. Additionally, we show that chemical compound treatments, targeting LRRK2 kinase activity or αSyn levels, are detectable when using ML classification based on multiple image-based phenotypes. We validated our approach using a second isogenic patient-derived SNCA gene triplication mDAN model which overexpresses αSyn. This phenotyping and classification strategy improves the practical exploitability of mDANs for disease modeling and the identification of novel LRRK2-associated drug targets.

Clinical differences between early-onset and mid-and-late-onset Parkinson's disease: Data analysis of the Hellenic Biobank of Parkinson's disease

BackgroundAge at onset is one of the most critical factors contributing to the clinical heterogeneity of Parkinson's disease (PD), and available evidence is rather conflicting. ObjectiveThe aim of this study is to investigate the clinical differences between early-onset PD (EOPD) and mid-and-late-onset PD (MLOPD) in the Greek population, based on the existing data of the Hellenic Biobank of PD (HBPD). MethodsHBPD contains information of PD cases from two centers in Greece during 2006–2017. Patients with the A53T mutation in the SNCA gene or mutations in the GBA1 gene were excluded. Associations between clinical characteristics (motor and non-motor symptoms, side of onset, first symptom, motor complications) and MLOPD versus EOPD were explored with a single logistic regression model adjusting for gender, family history of PD, disease and dopaminergic therapy duration, disease severity (UPDRS III), levodopa equivalent daily dose, as well as each of the other clinical characteristics. Results675 patients (129 EOPD, 546 MLOPD) were included. EOPD was more frequently associated with dystonia (OR 0.19, 95% CI 0.08–0.50, p < 0.01) and motor complications (0.23, 0.07–0.76, 0.02), compared to MLOPD. Bilateral onset (9.38, 1.05–84.04, 0.045) and autonomic dysfunction (2.31, 1.04–5.11, 0.04) were more frequently associated with MLOPD. ConclusionsEOPD and MLOPD display distinct clinical profiles, regarding motor and non-motor symptoms, side of onset and motor complications in the Greek population. These differences may reflect diverse pathophysiological backgrounds, potentially attributed to genetic or age-related epigenetic influences.

Genotypic-Phenotypic Analysis, Metabolic Profiling and Clinical Correlations in Parkinson's Disease Patients from Tamil Nadu Population, India.

Parkinson's disease (PD) is an ageing disorder caused by dopaminergic neuron depletion with age. Growing research in the field of metabolomics is expected to play a major role in PD diagnosis, prognosis and therapeutic development. In this study, we looked at how SNCA and GBA1 gene mutations, as well as metabolomic abnormalities of kynurenine and cholesterol metabolites, were linked to alpha-synuclein (α-syn) and clinical characteristics in three different PD age groups. In all three age groups, a metabolomics analysis revealed an increased amount of 27-hydroxycholesterol (27-OHC) and a lower level of kynurenic acid (KYNA). The effect of 27-OHC on SNCA and GBA1 modifications was shown to be significant (P < 0.05) only in the A53T variant of the SNCA gene in late-onset and early-onset PD groups, whereas GBA1 variants were not. Based on the findings, we observed that the increase in 27-OHC would have elevated α-syn expression, which triggered the changes in the SNCA gene but not in the GBA1 gene. Missense variations in the SNCA and GBA1 genes were investigated using the sequencing technique. SNCA mutation A53T has been linked to increased PD symptoms, but there is no phenotypic link between GBA1 and PD. As a result of the data, we hypothesise that cholesterol and kynurenine metabolites play an important role in PD, with the metabolite 27-OHC potentially serving as a PD biomarker. These findings will aid in the investigation of pathogenic causes as well as the development of therapeutic and preventative measures for PD.

Lipid level alteration in human and cellular models of alpha synuclein mutations

Lipid profiles in biological fluids from patients with Parkinson’s disease (PD) are increasingly investigated in search of biomarkers. However, the lipid profiles in genetic PD remain to be determined, a gap of knowledge of particular interest in PD associated with mutant α-synuclein (SNCA), given the known relationship between this protein and lipids. The objective of this research is to identify serum lipid composition from SNCA A53T mutation carriers and to compare these alterations to those found in cells and transgenic mice carrying the same genetic mutation. We conducted an unbiased lipidomic analysis of 530 lipid species from 34 lipid classes in serum of 30 participants with SNCA mutation with and without PD and 30 healthy controls. The primary analysis was done between 22 PD patients with SNCA+ (SNCA+/PD+) and 30 controls using machine-learning algorithms and traditional statistics. We also analyzed the lipid composition of human clonal-cell lines and tissue from transgenic mice overexpressing the same SNCA mutation. We identified specific lipid classes that best discriminate between SNCA+/PD+ patients and healthy controls and found certain lipid species, mainly from the glycerophosphatidylcholine and triradylglycerol classes, that are most contributory to this discrimination. Most of these alterations were also present in human derived cells and transgenic mice carrying the same mutation. Our combination of lipidomic and machine learning analyses revealed alterations in glycerophosphatidylcholine and triradylglycerol in sera from PD patients as well as cells and tissues expressing mutant α-Syn. Further investigations are needed to establish the pathogenic significance of these α-Syn-associated lipid changes.

Biomarker of Neuroinflammation in Parkinson's Disease.

Parkinson’s disease (PD) is caused by abnormal accumulation of α-synuclein in dopaminergic neurons of the substantia nigra, which subsequently causes motor symptoms. Neuroinflammation plays a vital role in the pathogenesis of neurodegeneration in PD. This neuroinflammatory neurodegeneration involves the activation of microglia, upregulation of proinflammatory factors, and gut microbiota. In this review, we summarized the recent findings on detection of PD by using inflammatory biomarkers, such as interleukin (IL)-1β, IL-2, IL-6, IL-10, tumor necrosis factor (TNF)-α; regulated upon activation, normal T cell expressed and presumably secreted (RANTES) and high-sensitivity c-reactive protein (hsCRP); and radiotracers such as [11C]PK11195 and [18F]-FEPPA, as well as by monitoring disease progression and the treatment response. Many PD-causing mutations in SNCA, LRRK2, PRKN, PINK1, and DJ-1 are also associated with neuroinflammation. Several anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs (NSAID), inhibitors of TNF-α and NLR family pyrin domain containing 3 (NLRP3), agonists of nuclear factor erythroid 2-related factor 2 (NRF2), peroxisome proliferator-activated receptor gamma (PPAR-γ), and steroids, have demonstrated neuroprotective effects in in vivo or in vitro PD models. Clinical trials applying objective biomarkers are required to investigate the therapeutic potential of anti-inflammatory medications for PD.

Subthalamic deep brain stimulation in Parkinson's disease with SNCA mutations: Based on the follow-up to 10years.

BackgroundsAlthough the short‐term efficacy of bilateral subthalamic deep brain stimulation (DBS) has been reported in a limited number of Parkinson's disease (PD) patients with SNCA mutations, there are no data for long‐term outcome.MethodsThis multicenter retrospective study investigated previously reported PD patients with SNCA mutations, implanted with bilateral subthalamic DBS. We compared demographic and clinical data at baseline and last follow‐up. Clinical data of motor and nonmotor symptoms and motor fluctuation were collected up to 10 years from DBS surgery.ResultsAmong four subjects, three had SNCA duplication and one had c.158C.A (p.A53E) mutation. The mean post‐implantation follow‐up duration was 5.4 ± 3.7 years. All patients with SNCA duplication showed favorable outcome, although one died from breast cancer 1.5 years after DBS. The patient with the missense mutation became wheelchair‐bound due to progressed axial, cognitive and psychiatric symptoms after 3.5 years from DBS despite the benefit on motor fluctuation.ConclusionBased on findings in our small cohort, subthalamic DBS could be beneficial for motor fluctuation in PD patients with SNCA mutations, especially those with SNCA duplication, and cognitive and psychiatric symptoms are important for the long‐term outcome of subthalamic DBS.

Cognitive Impairment in Genetic Parkinson's Disease.

Cognitive impairment is common in idiopathic Parkinson's disease (PD). Knowledge of the contribution of genetics to cognition in PD is increasing in the last decades. Monogenic forms of genetic PD show distinct cognitive profiles and rate of cognitive decline progression. Cognitive impairment is higher in GBA- and SNCA-associated PD, lower in Parkin- and PINK1-PD, and possibly milder in LRRK2-PD. In this review, we summarize data regarding cognitive function on clinical studies, neuroimaging, and biological markers of cognitive decline in autosomal dominant PD linked to mutations in LRRK2 and SNCA, autosomal recessive PD linked to Parkin and PINK1, and also PD linked to GBA mutations.