Snca

Parkinson's disease (PD) is a common age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the midbrain. A hallmark of both familial and sporadic PD is the presence of Lewy body inclusions composed mainly of aggregated α-synuclein (α-syn), a presynaptic protein encoded by the SNCA gene. The mechanisms driving the relationship between α-syn accumulation and neurodegeneration are not completely understood, although recent evidence indicates that multiple branches of the proteostasis pathway are simultaneously perturbed when α-syn aberrantly accumulates within neurons...

Parkinson's disease (PD) is a neurodegenerative disorder caused by complex genetic and environmental factors. Genome-edited human pluripotent stem cells (hPSCs) offer the uniique potential to advance our understanding of PD etiology by providing disease-relevant cell-types carrying patient mutations along with isogenic control cells. To facilitate this experimental approach, we generated a collection of 55 cell lines genetically engineered to harbor mutations in genes associated with monogenic PD ( SNCA A53T, SNCA A30P, PRKN Ex3del, PINK1 Q129X, DJ1/PARK7 Ex1-5del, LRRK2 G2019S, ATP13A2 FS, FBXO7 R498X/FS, DNAJC6 c...

Clinical investigations showed that individuals with Alcohol Use Disorder (AUD) have worse Neurological Disease (ND) development, pointing to possible pathogenic relationships between AUD and NDs. It remains difficult to identify risk factors that are predisposing between AUD and NDs. In order to fix these issues, we created the bioinformatics pipeline and network-based approaches for employing unbiased methods to discover genes abnormally stated in both AUD and NDs and to pinpoint some of the common molecular pathways that might underlie AUD and ND interaction...

Dysregulated Alzheimer's disease (AD)-associated protein expression is reported in polycystic ovary syndrome (PCOS), paralleling the expression reported in type 2 diabetes (T2D). We hypothesized, however, that these proteins would not differ between women with non-obese and non-insulin resistant PCOS compared to matched control subjects. We measured plasma amyloid-related proteins levels (Amyloid-precursor protein (APP), alpha-synuclein (SNCA), amyloid P-component (APCS), Pappalysin (PAPPA), Microtubule-associated protein tau (MAPT), apolipoprotein E (apoE), apoE2, apoE3, apoE4, Serum amyloid A (SAA), Noggin (NOG) and apoA1) in weight and aged-matched non-obese PCOS ( n = 24) and control ( n = 24) women...

INTRODUCTION: Metabolomics and proteomics are two growing fields of science which may shed light on the molecular mechanisms that contribute to neurodegenerative diseases. Studies focusing on these aspects can reveal specific metabolites and proteins that can halt or reverse the progressive neurodegenerative process leading to dopaminergic cell death in the brain. AREAS COVERED: In this article, an overview of the current status of metabolomic and proteomic profiling in the neurodegenerative disease such as Parkinson's disease (PD) is presented...

INTRODUCTION: Genetic studies conducted over the past four decades have provided us with a detailed catalog of genes that play critical roles in the etiology of Alzheimer's disease (AD) and related dementias (ADRDs). Despite this progress, as a field we have had only limited success in incorporating this rich complexity of human AD/ADRD genetics findings into our animal models of these diseases. Our primary goal for the gene replacement (GR)-AD project is to develop mouse lines that model the genetics of AD/ADRD as closely as possible...

BACKGROUND: Genetic underpinnings in Parkinson's disease (PD) and parkinsonian syndromes are challenging, and recent discoveries regarding their genetic pathways have led to potential gene-specific treatment trials. CASES: We report 3 X-linked levodopa (l-dopa)-responsive parkinsonism-epilepsy syndrome cases due to a hemizygous variant in the phosphoglycerate kinase 1 (PGK1) gene. The likely pathogenic variant NM_000291.4 (PGK1):c.950G > A;p.(Gly317Asp) was identified in a hemizygous state...

Alpha-synuclein (αSyn) protein levels correlate with the risk and severity of Parkinson's disease and related neurodegenerative diseases. Lowering αSyn is being actively investigated as a therapeutic modality. Here, we systematically map the regulatory network that controls endogenous αSyn using sequential CRISPR-knockout and -interference screens in an αSyn gene ( SNCA )-tagged cell line and induced pluripotent stem cell-derived neurons (iNeurons). We uncover αSyn modifiers at multiple regulatory layers, with amino-terminal acetyltransferase B (NatB) enzymes being the most potent endogenous αSyn modifiers in both cell lines...

Dementia with Lewy bodies (DLB) is a significant public health issue. It is the second most common neurodegenerative dementia and presents with severe neuropsychiatric symptoms. Genomic and transcriptomic analyses have provided some insight into disease pathology. Variants within SNCA , GBA , APOE , SNCB , and MAPT have been shown to be associated with DLB in repeated genomic studies. Transcriptomic analysis, conducted predominantly on candidate genes, has identified signatures of synuclein aggregation, protein degradation, amyloid deposition, neuroinflammation, mitochondrial dysfunction, and the upregulation of heat-shock proteins in DLB...

The misfolding and aggregation of α-synuclein is linked to a family of neurodegenerative disorders known as synucleinopathies, the most prominent of which is Parkinson's disease (PD). Understanding the aggregation process of α-synuclein from a mechanistic point of view is thus of key importance. SNCA , the gene encoding α-synuclein, comprises six exons and produces various isoforms through alternative splicing. The most abundant isoform is expressed as a 140-amino acid protein (αSyn-140), while three other isoforms, αSyn-126, αSyn-112, and αSyn-98, are generated by skipping exon 3, exon 5, or both exons, respectively...

Genome-wide association studies have identified thousands of single nucleotide polymorphisms that associate with increased risk for Parkinson's disease (PD), but the functions of most of them are unknown. Using assay for transposase-accessible chromatin (ATAC) and H3K27ac chromatin immunoprecipitation (ChIP) sequencing data, we identified 73 regulatory elements in microglia that overlap PD risk SNPs. To determine the target genes of a "risk enhancer" within intron two of SNCA , we used CRISPR-Cas9 to delete the open chromatin region where two PD risk SNPs reside...

Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, the first being Alzheimer's disease. Patients with PD have a loss of dopaminergic neurons in the substantia nigra of the basal ganglia, which controls voluntary movements, causing a motor impairment as a result of dopaminergic signaling impairment. Studies have shown that mutations in several genes, such as SNCA, PARK2, PINK1, DJ-1, ATP13A2, and LRRK2, and the exposure to neurotoxic agents can potentially increase the chances of PD development...

BACKGROUND: In the era of modern medicine, where high-throughput sequencing techniques are readily available, it is desirable to elucidate the role of genetic background in patients with Parkinson's Disease (PD) undergoing Deep Brain Stimulation (DBS). Genetic stratification of PD patients undergoing DBS may assist in patient selection and prediction of clinical outcomes and complement existing selection procedures such as levodopa challenge testing. OBJECTIVE: To capture a broad spectrum of motor and non-motor DBS outcomes in genetic PD patients with data from the recently updated literature...

BACKGROUND: Little is known about the pathogenesis of Bipolar Disorder, and even less is known about the genetic differences between its subtypes. Bipolar Disorder is classified into different subtypes, which present different symptoms and lifetime courses. While genetic studies have been conducted in Bipolar Disorder, most examined the gene expression of only Bipolar Disorder Type 1. Studies that include Bipolar Disorder Type 1 and Bipolar Disorder Type 2 often fail to differentiate them into separate conditions...

Parkinson's disease (PD) is a complex, progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain. Despite extensive research efforts, the molecular and cellular changes that precede neurodegeneration in PD are poorly understood. To address this, here we describe the use of patient specific human midbrain organoids harboring the SNCA triplication to investigate mechanisms underlying dopaminergic degeneration. Our midbrain organoid model recapitulates key pathological hallmarks of PD, including the aggregation of α-synuclein and the progressive loss of dopaminergic neurons...

Atypical parkinsonism (AP) is a group of complex neurodegenerative disorders with marked clinical and pathophysiological heterogeneity. The use of systems biology tools may contribute to the characterization of hub-bottleneck genes, and the identification of its biological pathways to broaden the understanding of the bases of these disorders. A systematic search was performed on the DisGeNET database, which integrates data from expert curated repositories, GWAS catalogues, animal models and the scientific literature...

Point mutations in the α-synuclein coding gene may lead to the development of Parkinson's disease (PD). PD is often accompanied by other psychiatric conditions, such as anxiety, depression, and drug use disorders, which typically emerge in adulthood. Some of these point mutations, such as SNCA and A30T, have been linked to behavioral effects that are not commonly associated with PD, especially regarding alcohol consumption patterns. In this study, we investigated whether the familial PD point mutation A53T is associated with changes in alcohol consumption behavior and emotional states at ages not yet characterized by α-synuclein accumulation...

INTRODUCTION: Cell therapeutic clinical trials using fetal mesencephalic tissue provided a proof-of-concept for regenerative therapy in patients with Parkinson's disease. Postmortem studies of patients with fetal grafts revealed that α-synuclein+ Lewy body (LB)-like inclusions emerged in long-term transplantation and might worsen clinical outcomes even if the grafts survived and innervated in the recipients. Various studies aimed at addressing whether host-derived α-synuclein could be transferred to the grafted neurons to assess α-synuclein+ inclusion appearance in the grafts...

Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes...

Polycystic ovary syndrome (PCOS) is the most common endocrine condition in women of reproductive age, and several risk factors found in PCOS are associated with an increased risk of Alzheimer's disease (AD). Proteins increased in AD have been reported to include fibronectin (FN) fragments 3 and 4 (FN1.3 and FN1.4, respectively) and ApoE. We hypothesized that Alzheimer-related proteins would be dysregulated in PCOS because of associated insulin resistance and obesity. In this comparative cross-sectional analysis, aptamer-based SomaScan proteomic analysis for the detection of plasma Alzheimer-related proteins was undertaken in a PCOS biobank of 143 women with PCOS and 97 control women...