SNCA Mutations Research Articles

Gene-corrected p.A30P SNCA patient-derived isogenic neurons rescue neuronal branching and function

Parkinson’s disease (PD) is characterised by the degeneration of A9 dopaminergic neurons and the pathological accumulation of alpha-synuclein. The p.A30P SNCA mutation generates the pathogenic form of the alpha-synuclein protein causing an autosomal-dominant form of PD. There are limited studies assessing pathogenic SNCA mutations in patient-derived isogenic cell models. Here we provide a functional assessment of dopaminergic neurons derived from a patient harbouring the p.A30P SNCA mutation. Using two clonal gene-corrected isogenic cell lines we identified image-based phenotypes showing impaired neuritic processes. The pathological neurons displayed impaired neuronal activity, reduced mitochondrial respiration, an energy deficit, vulnerability to rotenone, and transcriptional alterations in lipid metabolism. Our data describes for the first time the mutation-only effect of the p.A30P SNCA mutation on neuronal function, supporting the use of isogenic cell lines in identifying image-based pathological phenotypes that can serve as an entry point for future disease-modifying compound screenings and drug discovery strategies.

The Impact of SNCA Variations and Its Product Alpha-Synuclein on Non-Motor Features of Parkinson’s Disease

Parkinson’s disease (PD) is a common and progressive neurodegenerative disease, caused by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which is clinically characterized by a constellation of motor and non-motor manifestations. The latter include hyposmia, constipation, depression, pain and, in later stages, cognitive decline and dysautonomia. The main pathological features of PD are neuronal loss and consequent accumulation of Lewy bodies (LB) in the surviving neurons. Alpha-synuclein (α-syn) is the main component of LB, and α-syn aggregation and accumulation perpetuate neuronal degeneration. Mutations in the α-syn gene (SNCA) were the first genetic cause of PD to be identified. Generally, patients carrying SNCA mutations present early-onset parkinsonism with severe and early non-motor symptoms, including cognitive decline. Several SNCA polymorphisms were also identified, and some of them showed association with non-motor manifestations. The functional role of these polymorphisms is only partially understood. In this review we explore the contribution of SNCA and its product, α-syn, in predisposing to the non-motor manifestations of PD.

Mutations in GBA, SNCA, and VPS35 are not associated with Alzheimer's disease in a Chinese population: a case-control study.

SNCA, GBA, and VPS35 are three common genes associated with Parkinson's disease. Previous studies have shown that these three genes may be associated with Alzheimer's disease (AD). However, it is unclear whether these genes increase the risk of AD in Chinese populations. In this study, we used a targeted gene sequencing panel to screen all the exon regions and the nearby sequences of GBA, SNCA, and VPS35 in a cohort including 721 AD patients and 365 healthy controls from China. The results revealed that neither common variants nor rare variants of these three genes were associated with AD in a Chinese population. These findings suggest that the mutations in GBA, SNCA, and VPS35 are not likely to play an important role in the genetic susceptibility to AD in Chinese populations. The study was approved by the Ethics Committee of Xiangya Hospital, Central South University, China on March 9, 2016 (approval No. 201603198).

A late-onset Parkinson's disease in tribes in India – A case report

Parkinson’s disease (PD) is a complex neurodegenerative disorder, where its prevalence do vary geographically. We observed a 54-year-old male who belongs to a tribal community from Tamil Nadu, India, was diagnosed with PD. Occupationally, he was a farmer exposed to pesticides in agricultural fields. The family history revealed that the patient's parents had a consanguineous marriage and that his father showed symptoms of tremor and bradykinesia along with memory loss. We initially examined the family history and assessed Unified Parkinson's Disease Rating Scale (UPDRS) and Hoehn and Yahr (HY) scaling which showed low UPDRS rate and stage 3 HY scaling. Further, we conducted the dopamine transporter imaging which revealed decreased tracer binding in the left caudate with negligible uptake in the left putamen. Furthermore, we found that the patient had low levels of uric acid (2.2 mg/dL) with SNCA mutation (A53T). Environmental factors such as pesticides and smoking might have contributed SNCA mutation with low levels of uric acid. Also, the chromosomal analysis using fluorescent in situ hybridization (FISH) technique showed 22q11.2 deletion which is very uncommon in late-onset PD. In conclusion, this case study revealed that there is a humongous role of both environmental exposures and genetics in the onset of the PD.

α-Synuclein Deposition in Sympathetic Nerve Fibers in Genetic Forms of Parkinson's Disease.

Cytoplasmic inclusions of α-synuclein (α-syn) in brainstem neurons are characteristic of idiopathic Parkinson's disease (PD). PD also entails α-syn buildup in sympathetic nerves. Among genetic forms of PD, the relative extents of sympathetic intraneuronal accumulation of α-syn have not been reported. This cross-sectional observational study compared magnitudes of intraneuronal deposition of α-syn in common and rare genetic forms of PD. α-Syn deposition was quantified by the α-syn-tyrosine hydroxylase colocalization index in C2 cervical skin biopsies from 65 subjects. These included 30 subjects with pathogenic mutations in SNCA (n=3), PRKN [biallelic (n=7) and monoallelic (n=3)], LRRK2 (n=7), GBA (n=7), or PARK7/DJ1 [biallelic (n=1) and monoallelic (n=2)]. Twenty-five of the mutation carriers had PD and five did not. Data were also analyzed from 19 patients with idiopathic PD and 16 control participants. α-Syn deposition varied as a function of genotype (F=16.7, P< 0.0001). It was above the control range in 100% of subjects with SNCA mutations, 100% with LRRK2 mutations, 95% with idiopathic PD, 83% with GBA mutations, and 0% with biallelic PRKN mutations. α-Syn deposition in the biallelic PRKN group was significantly higher than in the control group. In addition, patients with biallelic PRKN mutations had higher α-syn deposition than their unaffected siblings. Individuals with SNCA, DJ-1, LRRK2, or GBA mutations have substantial intraneuronal α-syn deposition in sympathetic noradrenergic nerves in skin biopsies, whereas those with biallelic PRKN mutations do not. Biallelic PRKN patients may have mildly increased α-syn deposition compared with control subjects. © 2021 International Parkinson and Movement Disorder Society.

Role of Alpha‐Synuclein in Parkinson's Disease

While Parkinson's Disease is a multifactorial disease, influenced by both genetics and the environment, alpha-synuclein was the first genetic factor to be linked to the disease. It has henceforth become a target in therapeutic research. A-synuclein is a 140 amino acid neuronal protein that primarily regulates synaptic activity. It is considered to be intrinsically disordered as it does not have a defined structure in aqueous solutions. However, the protein forms α-helical structures when it binds to negatively charged lipids, such as phospholipids in cell membranes. Α-synuclein is a member of the synculein protein family, a group of three neuronal proteins with a highly conserved alpha-helical lipid binding domain. Synucleins have been associated with a number of neurodegenerative disorders, including Parkinson's Disease (PD) and Alzheimer's Disease (AD), as well as some cancers. A-synuclein is unique in the synuclein family for its non-amyloid component (NAC) region, which has been linked to the formation of Lewy bodies. The wild type form of α-synuclein is coded from the SNCA gene. This form has several functions, but it primarily functions as a presynaptic protein that controls neurotransmitter release by acting as a chaperone in the folding of Soluble NSF Attachment Protein Receptors (SNAREs). SNAREs mediate vesicle fusion with membranes, while α-synuclein increases local Ca2+ release from microdomains to trigger ATP-induced exocytosis. Certain mutations in SNCA cause α-synuclein to polymerize into protofibrils that eventually coalesce into fibrils, a process called α-synuclein aggregation. Aggregation of α-synuclein leads to the creation of Lewy bodies, toxic clumps in the brains of patients with PD. PD is a progressive neurodegenerative disorder that affects movement. Common symptoms include bradykinesia, muscular rigidity, and tremor. Some studies have shown that deleting the NAC region prevented aggregation of α-synuclein. Other α-synuclein therapies have used receptor blocking strategies to inhibit the spread of the protein to other parts of the brain. There are also a variety of therapies that focus on preventing aggregation by decreasing the amount of α-synuclein in the brain. While such therapies have shown positive results in fruit flies, mice, and rats, human trials have not been conducted. Medications to control symptoms are the main treatment for PD; these medications typically work by increasing or acting as a substitute for dopamine, as PD patients have low dopamine concentrations. In severe cases, surgeries like deep brain stimulations have helped to lessen tremors. Patients are encouraged to make lifestyle changes, such as uptaking aerobic exercise or physical therapy, which can improve symptoms. Further research on the relationship between α-synuclein and Parkinson's Disease is required before human trials can begin. Nonetheless, the results of therapeutic studies have been promising.

Genotype-Phenotype Relations for the Atypical Parkinsonism Genes: MDSGene Systematic Review.

This Movement Disorder Society Genetic mutation database Systematic Review focuses on monogenic atypical parkinsonism with mutations in the ATP13A2, DCTN1, DNAJC6, FBXO7, SYNJ1, and VPS13C genes. We screened 673 citations and extracted genotypic and phenotypic data for 140 patients (73 families) from 77 publications. In an exploratory fashion, we applied an automated classification procedure via an ensemble of bootstrap-aggregated (“bagged”) decision trees to distinguish these 6 forms of monogenic atypical parkinsonism and found a high accuracy of 86.5% (95% CI, 86.3%–86.7%) based on the following 10 clinical variables: age at onset, spasticity and pyramidal signs, hypoventilation, decreased body weight, minimyoclonus, vertical gaze palsy, autonomic symptoms, other nonmotor symptoms, levodopa response quantification, and cognitive decline. Comparing monogenic atypical with monogenic typical parkinsonism using 2063 data sets from Movement Disorder Society Genetic mutation database on patients with SNCA, LRRK2, VPS35, Parkin, PINK1, and DJ-1 mutations, the age at onset was earlier in monogenic atypical parkinsonism (24 vs 40 years; P = 1.2647 × 10−12) and levodopa response less favorable than in patients with monogenic typical presentations (49% vs 93%). In addition, we compared monogenic to nonmonogenic atypical parkinsonism using data from 362 patients with progressive supranuclear gaze palsy, corticobasal degeneration, multiple system atrophy, or frontotemporal lobar degeneration. Although these conditions share many clinical features with the monogenic atypical forms, they can typically be distinguished based on their later median age at onset (64 years; IQR, 57–70 years). In conclusion, age at onset, presence of specific signs, and degree of levodopa response inform differential diagnostic considerations and genetic testing indications in atypical forms of parkinsonism.

Analysis of α-Synuclein in Exosomes.

Alpha synuclein (α-Syn), a presynaptic protein with unknown function, is accumulated in Lewy bodies/neurites that are one of the hallmark pathologies of Parkinson's disease (PD). Missense or multiplication mutations in SNCA, which codes α-Syn, result in a genetic form of PD, further indicating the involvement of α-Syn in PD pathogenesis. Recent pathological and experimental studies suggest that α-Syn possesses a secretory feature, as it is detected in the culture media, in the cerebrospinal fluid, and even in the blood. Secreted α-Syn can spread throughout the body and invade the CNS, disseminating the α-Syn associated pathology. Exosomes are small extracellular vesicles that carry many proteins, lipids, or miRNA. We and others have discovered α-Syn in exosomes and revealed that exosomes may regulate intracellular α-Syn levels by transporting outside the cells. In this chapter, we describe a protocol to measure α-Syn levels in exosomes.

Identification of Somatic Mutations in Dementia-related Genes in Cancer Patients.

Dementia is an overall term of brain diseases, including Alzheimer's disease (AD), tauopathies and synucleinopathies. To date, somatic mutations in dementia-related genes, including the amyloid precursor protein (APP) gene, presenilin 1 (PSEN1) gene, PSEN2 gene, microtubule- associated protein tau (MAPT) gene, alpha-synuclein (SNCA) gene and leucine-rich repeat kinase 2 (LRRK2) gene, have been considered one cause of dementia. We have questioned the impact of somatic mutations in dementia-related genes on cancer. In the present study, we investigated somatic mutations in the APP, PSEN1, PSEN2, MAPT, SNCA and LRRK2 genes and the impact of these somatic mutations. From The Cancer Genome Atlas (TCGA) database, we found 1,643 somatic mutations in the APP, PSEN1, PSEN2, MAPT, SNCA and LRRK2 genes in cancer patients. Strikingly, compared to the distributions of cancer types in total cancer patients, somatic mutations in the dementia-related genes showed an extremely low distribution in glioblastoma patients. To the best of our knowledge, this is the first investigation of dementia-related genes in cancer patients.

REM sleep behavior disorder and other sleep abnormalities in p. A53T SNCA mutation carriers.

Τo assess whether REM Sleep Behavior Disorder (RBD) and other sleep abnormalities occur in carriers of the p.A53T alpha-synuclein gene (SNCA) mutation, using both subjective and objective measures. We have assessed 15 p.A53T carriers (10 manifesting Parkinson's Disease [PD-A53T] and 5 asymptomatic carriers) with simultaneous Video-PSG (polysomnography) recording, the Epworth Sleepiness Scale (ESS) for daytime sleepiness, the Athens Insomnia Scale (AIS), the RBD Screening Questionnaire (RBDSQ) for clinical features of RBD, the Montreal Cognitive Assessment (MOCA) for cognition and the University of Pennsylvania Smell Identification Test (UPSIT) for olfaction. In our cohort, 90% of PD carriers had at least one sleep disorder and 40% had two: 4 RBD, 1 Periodic Limb Movements (PLM), 1 RBD plus PLM, 2 RBD plus moderate Obstructive Sleep Apnea (OSA), and 1 moderate OSA plus Restless Leg Syndrome. No asymptomatic carrier manifested a confirmed sleep disorder. 6/7 PD carriers with RBD had abnormal olfactory testing and 4/7 MOCA below cut off. There was a correlation of both impaired olfaction and cognition with RBD. RBD occurs in the majority of PD-A53T, in contrast to most other genetic forms of PD, in which RBD is uncommon. The paucity of a sleep disorder in the asymptomatic carriers suggests that such carriers have not yet reached the prodromal phase when such sleep disorders manifest. Hyposmia in almost all subjects with RBD and cognitive decline in most of them are indicative of the general pattern of disease progression, which however is not uniform.

The mechanistic role of alpha-synuclein in the nucleus: impaired nuclear function caused by familial Parkinson's disease SNCA mutations.

Alpha-synuclein SNCA has been implicated in the etiology of Parkinson's disease (PD); however, the normal function of alpha-synuclein protein and the pathway that mediates its pathogenic effect is yet to be discovered. We investigated the mechanistic role of SNCA in the nucleus utilizing isogenic human-induced pluripotent stem cells-derived neurons from PD patients with autosomal dominant mutations, A53T and SNCA-triplication, and their corresponding corrected lines by genome- and epigenome-editing. Comparisons of shape and integrity of the nuclear envelope and its resistance to stresses found that both mutations result in similar nuclear envelope perturbations that were reversed in the isogenic mutation-corrected cells. Further mechanistic studies showed that SNCA mutation has adverse effects on the nucleus by trapping Ras-related nuclear protein (RAN) and preventing it from transporting key nuclear proteins such as, DNMT3A, for maintaining normal nuclear function. For the first time, we proposed that α-syn interacts with RAN and normally functions in the nucleocytoplasmic transport while exerts its pathogenic effect by sequestering RAN. We suggest that defects in the nucleocytoplasmic transport components may be a general pathomechanistic driver of neurodegenerative diseases.

Generation of two iPS cell lines (HIHDNDi001-A and HIHDNDi001-B) from a Parkinson's disease patient carrying the heterozygous p.A30P mutation in SNCA.

Dermal fibroblasts from a patient carrying a heterozygous c.88G>C mutation in the SNCA gene that encodes alpha-synuclein were reprogrammed to pluripotency by retroviruses. This pathogenic mutation generates the p.A30P form of the alpha-synuclein protein leading to autosomal dominantly inherited Parkinson's disease (PD). Two clonal iPS cell lines were generated (A30P-3 and A30P-4) and characterised by validating the silencing of viral transgenes, the expression of endogenous pluripotency genes, directed differentiation into three germ layers in-vitro and a stable molecular genotype. These iPSC lines will serve as a valuable resource in determining the role of the p.A30P SNCA mutation in PD pathogenesis.

Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort.

LRRK2, SNCA, and VPS35 are unequivocally associated with autosomal dominant Parkinson's disease (PD). We evaluated the prevalence of LRRK2, SNCA, and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1,805 index cases (592 with autosomal dominant inheritance and 1,213 isolated cases) since 1990. All probands were screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0 vs. 7.3%; OR 1.7, 95% CI [1.2–2.4], p = 0.001). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0–2.1], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤ 50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.

LRRK2 and α-Synuclein: Distinct or Synergistic Players in Parkinson's Disease?

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by prominent degeneration of dopaminergic neurons in the substantia nigra and aggregation of the protein α-synuclein within intraneuronal inclusions known as Lewy bodies. Ninety percent of PD cases are idiopathic while the remaining 10% are associated with gene mutations that affect cellular functions ranging from kinase activity to mitochondrial quality control, hinting at a multifactorial disease process. Mutations in LRRK2 and SNCA (the gene coding for α-synuclein) cause monogenic forms of autosomal dominant PD, and polymorphisms in either gene are also associated with increased risk of idiopathic PD. Although Lewy bodies are a defining neuropathological feature of PD, an appreciable subset of patients with LRRK2 mutations present with a clinical phenotype indistinguishable from idiopathic PD but lack Lewy pathology at autopsy, suggesting that LRRK2-mediated PD may occur independently of α-synuclein aggregation. Here, we examine whether LRRK2 and α-synuclein, as mediators of neurodegeneration in PD, exist in common or distinct pathways. Specifically, we review evidence from preclinical models and human neuropathological studies examining interactions between the two proteins. Elucidating the degree of interplay between LRRK2 and α-synuclein will be necessary for treatment stratification once effective targeted disease-modifying therapies are developed.

Long-Term Outcomes of Genetic Parkinson's Disease.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects 1–2% of people by the age of 70 years. Age is the most important risk factor, and most cases are sporadic without any known environmental or genetic causes. Since the late 1990s, mutations in the genes SNCA, PRKN, LRRK2, PINK1, DJ-1, VPS35, and GBA have been shown to be important risk factors for PD. In addition, common variants with small effect sizes are now recognized to modulate the risk for PD. Most studies in genetic PD have focused on finding new genes, but few have studied the long-term outcome of patients with the specific genetic PD forms. Patients with known genetic PD have now been followed for more than 20 years, and we see that they may have distinct and different prognoses. New therapeutic possibilities are emerging based on the genetic cause underlying the disease. Future medication may be based on the pathophysiology individualized to the patient’s genetic background. The challenge is to find the biological consequences of different genetic variants. In this review, the clinical patterns and long-term prognoses of the most common genetic PD variants are presented.

Clinicopathologic and genetic features of multiple system atrophy with Lewy body disease.

Background: Abnormal aggregates of α‐synuclein are pathologic hallmarks of multiple system atrophy (MSA) and Lewy body disease (LBD). LBD sometimes coexists with MSA, but the impact of co‐pathology, particularly diffuse LBD, on presentation of MSA has not been studied. We aimed to determine the frequency and clinicopathologic features of MSA with LBD (MSA+LBD). Methods: Using hematoxylin & eosin and α‐synuclein‐immunostained slides, we assessed the distribution and severity of LBD in 230 autopsy‐confirmed MSA patients collected from 1998 to 2018. Alzheimer‐type pathology was assessed to assign the likelihood of clinical presentations of dementia with Lewy body (DLB) using the consensus criteria for DLB. We reviewed medical records to characterize clinicopathologic features of MSA+LBD. Genetic risk factors for LBD, including APOE ε4 allele and mutations in GBA, SNCA, LRRK2, and VPS35, were analyzed. Results: LBD was observed in 11 MSA patients (5%); seven were brainstem type, three were transitional type, and one was diffuse type. The latter four had an intermediate or high likelihood of DLB. Three of the four had an antemortem diagnosis of Parkinson’s disease with dementia (PDD) or clinically probable DLB. Two patients had neuronal loss in the substantia nigra, but not in striatal or olivocerebellar systems with widespread glial cytoplasmic inclusions, consistent with minimal change MSA. In these cases, LBD was considered the primary pathology, and MSA was considered coincidental. APOE ε4 allele frequency was not different between MSA+LBD and MSA without LBD. Two of nine MSA+LBD patients had a risk variant of GBA (p.T408M and p.E365K). Conclusions: Although rare, MSA with transitional or diffuse LBD can develop clinical features of PDD or DLB. Minimal change MSA can be interpreted as a coincidental, but distinct, α‐synucleinopathy in a subset of patients with diffuse LBD.

Serum Uric Acid Level as a Biomarker in Idiopathic and Genetic (p.A53T Alpha-Synuclein Carriers) Parkinson's Disease: Data from the PPMI Study.

Blood uric acid level represents an emerging biomarker in Parkinson's disease (PD). Whether uric acid levels change in genetic forms of PD is just beginning to be explored. The aim of the present study was to assess differences in serum uric acid level among PD patients harboring the p.A53T mutation in the alpha-synuclein gene, idiopathic PD, and healthy controls. Longitudinal 5-year serum uric acid measurement data of 369 de novo idiopathic PD patients and 174 age- and gender-matched healthy controls have been downloaded from the Parkinson's Progression Markers Initiative (PPMI) database. Furthermore, we assessed baseline serum uric acid measurements of 24 p.A53T alpha-synuclein PD patients enrolled in PPMI and followed in our site as compared to 24 age-, gender- and disease duration-matched sporadic PD patients and 24 healthy controls. Longitudinal serum uric acid measurements did not differ statistically between idiopathic PD patients and healthy controls (despite a trend for lower uric acid in the PD group) (p = 0.879). This was also true when male and female subgroups were assessed separately. The p.A53T SNCA mutation carrier PD group exhibited lower baseline serum uric acid level as compared to their matched healthy controls (p = 0.025). In the present study we did not replicate the established lower serum uric acid measurements in PD patients as compared to controls using PPMI data, possibly due to the fact that PD patients in baseline visit were de novo and the average disease duration was shorter than that observed in most epidemiological PD studies. The faster progression rate and increased disease severity in p.A53T PD possibly correlate with the lower serum uric acid observed in this subgroup.

Alterations in α-synuclein and PINK1 expression reduce neurite length and induce mitochondrial fission and Golgi fragmentation in midbrain neurons

Accumulation of α-synuclein is a pathological hallmark of Parkinson’s disease (PD) and has been linked to reductions in neurite length and axonal degeneration of midbrain dopaminergic neurons. Mutations in SNCA, which encodes α-synuclein, and loss of function mutations in PTEN-induced putative kinase-1 (PINK1) cause familial PD. There is a need to identify the mechanisms by which α-synuclein overexpression and the loss of PINK1 induce neurodegeneration in PD. To do this, we employed rat ventral midbrain cultures to investigate the effects of overexpression of wildtype or mutant (A53T) α-synuclein, and of siRNA knockdown of PINK1, on neurite length and on mitochondrial and Golgi integrity. We found reduced neurite length and increased levels of both Golgi fragmentation and mitochondrial fission in response to overexpression of wildtype or mutant α-synuclein, and to PINK1 knockdown. Reductions in neurite length induced by these two PD risk genes were significantly correlated with increases in Golgi fragmentation and mitochondrial fission. Combined α-synuclein overexpression and PINK1 knockdown induced a greater reduction in neurite length and increase in Golgi fragmentation, than either alone. This study provides novel evidence that α-synuclein overexpression and PINK1 deletion converge to induce significant increases in Golgi fragmentation and mitochondrial fission in midbrain neurons, that are correlated with decreases in neurite length. This highlights the need for further studies on these converging mechanisms in dopaminergic neurodegeneration in PD.

Cognitive and psychiatric symptoms in genetically determined Parkinson's disease: a systematic review.

The aim was to review the existing reports on cognitive and behavioural symptoms in monogenic forms of Parkinson's disease (PD) and to identify recurring patterns of clinical manifestations in those with specific mutations. A systematic literature search was conducted to retrieve observational studies of monogenic PD. Data pertaining to cognitive and psychiatric manifestations were extracted using standardized templates. The PRISMA guidelines were followed. Of the 1889 citations retrieved, 95 studies on PD-related gene mutations were included: 35 in SNCA, 35 in LRRK2, four in VPS35, 10 in Parkin, three in DJ1 and eight in PINK1. Nineteen studies (20%) provided adequate data from comprehensive cognitive assessment and 31 studies (32.6%) outlined psychiatric manifestations through the use of neuropsychiatric scales. Cognitive impairment was reported in all monogenic PD forms with variable rates (58.8% PINK1, 53.9% SNCA, 50% DJ1, 29.2% VPS35, 15.7% LRRK2 and 7.4% Parkin). In this regard, executive functions and attention were the domains most affected. With respect to psychiatric symptoms, depression was the most frequent symptom, occurring in 37.5% of PINK1 cases and 41.7% of VPS35 and LRRK2 cases. Co-occurrence of cognitive decline with visual hallucinations was evidenced. Widespread accumulation of Lewy bodies, distinctive of SNCA, PINK1 and DJ1 mutations, results in higher rates of cognitive impairment. Similarly, a higher degree of visual hallucinations is observed in SNCA mutations, probably owing to the more widespread accumulation. The lower rates of α-synuclein pathology in LRRK2 and Parkin may underpin the more benign disease course in these patients.

Behavioural and dopaminergic changes in double mutated human A30P*A53T alpha-synuclein transgenic mouse model of Parkinson\xb4s disease

Alpha-synuclein (aSyn) is the main component of Lewy bodies, the histopathological marker in Parkinson’s disease (PD), and point mutations and multiplications of the aSyn coding SNCA gene correlate with early onset PD. Therefore, various transgenic mouse models overexpressing native or point-mutated aSyn have been developed. Although these models show highly increased aSyn expression they rarely capture dopaminergic cell loss and show a behavioural phenotype only at old age, whereas SNCA mutations are risk factors for PD with earlier onset. The aim of our study was to re-characterize a transgenic mouse strain carrying both A30P and A53T mutated human aSyn. Our study revealed decreased locomotor activity for homozygous transgenic mice starting from 3 months of age which was different from previous studies with this mouse strain that had behavioural deficits starting only after 7–9 months. Additionally, we found a decreased amphetamine response in locomotor activity and decreased extracellular dopaminergic markers in the striatum and substantia nigra with significantly elevated levels of aSyn oligomers. In conclusion, homozygous transgenic A30P*A53T aSyn mice capture several phenotypes of PD with early onset and could be a useful tool for aSyn studies.