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At least 19 recordsLinked to original sources
PubMed1997

Binding of Abeta to alpha- and beta-synucleins: identification of segments in alpha-synuclein/NAC precursor that bind Abeta and NAC.

NAC, a 35-residue peptide derived from the neuronal protein alpha-synuclein/NAC precursor, is tightly associated with Abeta fibrils in Alzheimer's disease amyloid, and alpha-synuclein has recently been shown to bind Abeta in vitro. We have studied the interaction between Abeta and synucleins, aiming at determining segments in alpha-synuclein that can account for the binding, as well as identifying a possible interaction between Abeta and the beta-type synuclein. We report that Abeta binds to native and recombinant alpha-synuclein, and to beta-synuclein in an SDS-sensitive interaction (IC50 approx. 20 microM), as determined by chemical cross-linking and solid-phase binding assays. alpha-Synuclein and beta-synuclein were found to stimulate Abeta-aggregation in vitro to the same extent. The synucleins also displayed Abeta-inhibitable binding of NAC and they were capable of forming dimers. Using proteolytic fragmentation of alpha-synuclein and cross-linking to 125I-Abeta, we identified two consecutive binding domains (residues 1-56 and 57-97) by Edman degradation and mass spectrometric analysis, and a synthetic peptide comprising residues 32-57 possessed Abeta-binding activity. To test further the possible significance in pathology, alpha-synuclein was biotinylated and shown to bind specifically to amyloid plaques in a brain with Alzheimer's disease. It is proposed that the multiple Abeta-binding sites in alpha-synuclein are involved in the development of amyloid plaques.

Amyloid↗
PubMed1995

Residues in the synuclein consensus motif of the alpha-synuclein fragment, NAC, participate in transglutaminase-catalysed cross-linking to Alzheimer-disease amyloid beta A4 peptide.

The widespread deposition of amyloid plaques is one of the hallmarks of Alzheimer disease (AD). A recently described component of amyloid plaques is the 35-residue peptide, non-A beta component of AD amyloid, which is derived from a larger intracellular neuronal constituent, alpha-synuclein. We demonstrate that transglutaminase catalyses the formation of the covalent non-A beta component of AD amyloid polymers in vitro as well as polymers with beta-amyloid peptide, the major constituent of AD plaques. The transglutaminase-reactive amino acid residues in the non-A beta component of AD amyloid were identified as Gln79 and Lys80. Lys80 is localized in a consensus motif Lys-Thr-Lys-Glu-Gly-Val, which is conserved in the synuclein gene family. Thus transglutaminase might be involved in the formation of insoluble amyloid deposits and participate in the modification of other members of the synuclein family.

Alzheimer Disease↗
PubMed1997

Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the alpha-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.

Age of Onset↗
PubMed1995

High-resolution mapping of SNCA encoding alpha-synuclein, the non-A beta component of Alzheimer's disease amyloid precursor, to human chromosome 4q21.3-->q22 by fluorescence in situ hybridization.

The human alpha-synuclein gene (SNCA) was previously identified as the non-A beta component of Alzheimer's disease amyloid precursor (NACP). A cosmid clone containing this gene has been isolated and mapped by FISH and high-resolution fluorescence banding to human chromosome 4q21.3-->q22.

Amyloid↗
PubMed2025

Longitudinal multi-omics in alpha-synuclein Drosophila model discriminates disease- from age-associated pathologies in Parkinson's disease.

Parkinson's disease (PD) starts decades before symptoms appear, usually in the later decades of life, when age-related changes are occurring. To identify molecular changes early in the disease course and distinguish PD pathologies from aging, we generated Drosophila expressing alpha-synuclein (αSyn) in neurons and performed longitudinal bulk transcriptomics and proteomics on brains at six time points across the lifespan and compared the data to healthy control flies as well as human post-mortem brain datasets. We found that translational and energy metabolism pathways were downregulated in αSyn flies at the earliest timepoints; comparison with the aged control flies suggests that elevated αSyn accelerates changes associated with normal aging. Unexpectedly, single-cell analysis at a mid-disease stage revealed that neurons upregulate protein synthesis and nonsense-mediated decay, while glia drive their overall downregulation. Longitudinal multi-omics approaches in animal models can thus help elucidate the molecular cascades underlying neurodegeneration vs. aging and co-pathologies.

Journal Article↗
PubMed1994

Identification of two distinct synucleins from human brain.

Two abundant proteins of 140 and 134 amino acids were purified and sequenced from human brain. They were identified through their reactivity on immunoblots with a partially characterised monoclonal antibody that recognises tau protein in a phosphorylation-dependent manner. The 140 amino acid protein is identical with the precursor of the non-A beta component of Alzheimer's disease amyloid which in turn is highly homologous to synuclein from Torpedo electroplaques and rat brain. The 134 amino acid protein is the human homologue of bovine phosphoneuroprotein 14; it is 61% identical in sequence to the 140 amino acid protein. The previously unrecognised homology between these two proteins defines a family of human brain synucleins. We refer to the 140 and 134 amino acid proteins as alpha-synuclein and beta-synuclein, respectively. Both synucleins are expressed predominantly in brain, where they are concentrated in presynaptic nerve terminals.

Alzheimer Disease↗
PubMed2026

Missense mutations in the SNCA gene: Molecular mechanisms and clinical implications.

The SNCA gene on chromosome 4 encodes the alpha-synuclein (αSyn) protein, which plays a central role in the pathogenesis of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While αSyn has established roles in synaptic vesicle dynamics and neuronal signaling, alterations in SNCA regulation and sequence contribute to protein misfolding, aggregation, and loss of function. Alterations in secondary and tertiary structure, as well as protein aggregation, affect biochemical interactions, ultimately leading to pathogenesis. This review outlines the molecular architecture of the SNCA gene, including regulatory regions, alternative splicing, and untranslated regions that influence αSyn expression and isoform diversity. Seven missense mutations of the SNCA gene are discussed in detail from the genomic level, extending to phenotypic presentations. These missense mutations have different effects on the aggregation kinetics and fibril formation. Specific genotype-phenotype correlations are evident, with mutations such as A30P and H50Q commonly resembling idiopathic PD, E46K strongly associated with DLB, and G51D, A53T, and A53E linked to atypical parkinsonism and MSA-like syndromes. Differences in age at onset, disease progression, cognitive involvement, and response to therapy further reflect mutation-specific effects and modifying influences of allelic dosage and epigenetic regulation. Collectively, these findings emphasize the importance of SNCA genetic variation in shaping disease phenotype and progression. Improving the understanding of SNCA genotype-phenotype relationships in future studies may facilitate earlier diagnosis, refine prognostic stratification, and support the development of targeted, disease-modifying therapies for synucleinopathies.

Molecular mechanisms↗
PubMed2025

CNV-Finder: Streamlining Copy Number Variation Discovery.

Copy Number Variations (CNVs) play pivotal roles in the etiology of complex diseases and are variable across diverse populations. Understanding the association between CNVs and disease susceptibility is significant in disease genetics research and often requires analysis of large sample sizes. One of the most cost-effective and scalable methods for detecting CNVs is based on normalized signal intensity values, such as Log R Ratio (LRR) and B Allele Frequency (BAF), from Illumina genotyping arrays. In this study, we present CNV-Finder, a novel pipeline integrating deep learning techniques on array data, specifically a Long Short-Term Memory (LSTM) network, to expedite the large-scale identification of CNVs within predefined genomic regions. This facilitates efficient prioritization of samples for time-consuming or costly subsequent analyses such as Multiplex Ligation-dependent Probe Amplification (MLPA), short-read, and long-read whole genome sequencing. We incorporate four genes to establish our methods-Parkin (PRKN), Leucine Rich Repeat And Ig Domain Containing 2 (LINGO2), Microtubule Associated Protein Tau (MAPT), and alpha-Synuclein (SNCA)-which may be relevant to neurological diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP), or related disorders such as essential tremor (ET). By training our models on expert-annotated samples and validating them across diverse cohorts, including those from the Global Parkinson's Genetics Program (GP2) and additional dementia-specific databases, we demonstrate the efficacy of CNV-Finder in accurately detecting deletions and duplications. Our pipeline outputs app-compatible files for visualization within CNV-Finder's interactive web application. This interface enables researchers to review predictions and filter displayed samples by model prediction values, LRR range, and variant count in order to explore or confirm results. Our pipeline integrates this human feedback to enhance model performance and reduce false positive rates. Through a series of comprehensive analyses and validations using visual inspection, MLPA, short-read, and long-read sequencing data, we demonstrate the robustness and adaptability of CNV-Finder in identifying CNVs with regions of varied size, probe density, and noise. Our findings highlight the significance of contextual understanding and human expertise in enhancing the precision of CNV identification, particularly in complex genomic regions like 17q21.31. The CNV-Finder pipeline is a scalable, publicly available resource for the scientific community, available on GitHub (https://github.com/GP2code/CNV-Finder; DOI 10.5281/zenodo.14182563). CNV-Finder not only expedites accurate candidate identification but also significantly reduces the manual workload for researchers, enabling future targeted validation and downstream analyses in regions or phenotypes of interest.

Copy Number Variation (CNV)↗
PubMed2025

Differential Expression of Erythrocyte Proteins in Patients with Alcohol Use Disorder.

Alcohol Use Disorder (AUD) poses global health challenges, and causes hematological alterations such as macrocytosis and oxidative stress. Disruption of protein structures by alcohol and/or its metabolites may exacerbate AUDs; proteomics can elucidate the underlying biological mechanisms. This study examined the proteins differentially expressed in the cytosol and membrane fractions of erythrocytes obtained from 30 male patients with AUD, comparing them to samples from 15 age- and BMI-matched social drinkers (SDs) and 15 non-drinkers (control). The analysis aimed to identify the molecular differences related to alcohol consumption. The AUD patient subgrouping was based on mean corpuscular volume (MCV), with 16 individuals classified as having a normal MCV and 14 having a high MCV. Proteins were separated via two-dimensional(2D)-gel electrophoresis, digested with trypsin, and identified via Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (TOF) mass spectrometry (MALDI-TOF/TOF). Additionally, levels of malondialdehyde and 4-hydroxyalkenals (MDA + HAE), reduced glutathione (GSH), oxidized glutathione (GSSG), serum carbohydrate-deficient transferrin (%CDT), disialotransferrin (%DST), and sialic acid (SA) were analyzed. The results showed increased MDA + HAE and decreased total thiols in AUD patients, with GSSG elevated and the GSH/GSSG ratio reduced in the AUD MCV-high subgroup. Serum %CDT, %DST, and SA were significantly higher in AUD. Compared to the control profiles, the AUD group exhibited differential protein expression. Few proteins, such as bisphosphoglycerate mutase, were downregulated in AUD versus control and SD, as well as in the MCV-high AUD subgroup. Conversely, endoplasmin and gelsolin were upregulated in AUD relative to control. Cytoskeletal proteins, including spectrin-alpha chain, actin cytoplasmic 2, were overexpressed in the AUD group and MCV-high AUD subgroup. Several proteins, such as 14-3-3 isoforms, alpha-synuclein, translation initiation factors, heat shock proteins, and others, were upregulated in the MCV-high AUD subgroup. Under-expressed proteins in this subgroup include band 3 anion transport protein, bisphosphoglycerate mutase, tropomyosin alpha-3 chain, uroporphyrinogen decarboxylase, and WD repeat-containing protein 1. Our findings highlight the specific changes in protein expression associated with oxidative stress, cytoskeletal alterations, and metabolic dysregulation, specifically in AUD patients with an elevated MCV. Understanding these mechanisms is crucial for developing targeted interventions and identifying biomarkers of alcohol-induced cellular damage. The complex interplay between oxidative stress, membrane composition, and cellular function illustrates how chronic alcohol exposure affects cellular physiology.

Humans↗
PubMed2026

Intra-locus coeruleus LPS administration induces anxiety-like behavior, thermal hyperalgesia, and striatal lysosomal alterations: Relevance to Parkinson's disease.

According to Braak's staging hypothesis, Parkinson's disease (PD) pathology may originate in extranigral regions, including the locus coeruleus (LC). In parallel, PD has been associated with lysosomal dysfunction. Here, we investigated whether intra-LC lipopolysaccharide (LPS) injection may produce behavioral alterations and lysosomal protein changes in the striatum and prefrontal cortex (PFC), regions critically implicated in PD pathology. Adult male Wistar rats received unilateral injections of saline or LPS (10 µg/2 µL) into the LC or striatum and were assessed for anxiety-like behavior, thermal hyperalgesia, and motor coordination. A separate cohort was sacrificed 15 days post-injection to assess lysosomal proteins (cathepsin D, β-glucocerebrosidase, Lysosomal Associated Membrane Protein 2 (LAMP2)) and α-synuclein (α-Syn). Intra-LC LPS induced anxiety-like behavior, reflected by reduced time spent in the center of the open field, and thermal hyperalgesia, as shown by shortened tail-flick latency, whereas intra-striatal LPS impaired locomotion and motor coordination, evidenced by reduced line crossings and decreased rotarod performance. Intra-LC but not intra-striatal LPS reduced LAMP2 levels in the striatum, while all other markers remained unchanged in both regions. These findings provide experimental support for Braak's hypothesis.

Animals↗
PubMed2026

Plasma cfDNA hypermethylation at SNCA intron 1 as a potential blood-based epigenetic signal in Parkinson's disease and multiple system atrophy.

BACKGROUND: The accumulation of α-synuclein (SNCA) in the central nervous system is a hallmark of Parkinson's disease (PD) and multiple system atrophy (MSA). SNCA intron 1 methylation is implicated in SNCA transcriptional regulation and may serve as a peripheral epigenetic signal in synucleinopathies. However, studies of SNCA methylation in leukocyte-derived DNA have yielded inconsistent results. We aimed to evaluate whether cell-free DNA (cfDNA)-based SNCA intron 1 methylation differs in PD or MSA compared with normal controls (NC). METHODS: Plasma cfDNA was collected from 105 patients with PD, 50 with MSA, and 114 NC. DNA methylation at CpG sites 10-17 was quantified by bisulfite pyrosequencing. Multivariable linear and logistic regression models, adjusted for age, sex, and education, were used to compare methylation levels and estimate odds ratios (ORs). RESULTS: Patients with PD exhibited hypermethylation at CpG site 14 and higher mean methylation across CpG sites 10-17 compared with NC. Patients with MSA showed hypermethylation at CpG sites 10, 12, 13, and 17 and elevated mean methylation. Elevated mean methylation was also observed in drug-naïve de novo PD and early-stage PD patients. Compared with the lowest tertile, the highest mean methylation tertile was associated with increased odds of PD (OR, 2.49; 95% CI, 1.08-5.92) and MSA (OR, 5.02; 95% CI, 1.58-18.00). CONCLUSION: Plasma cfDNA SNCA intron 1 hypermethylation is associated with PD and MSA and detectable in drug-naïve and early-stage PD. It may represent a peripheral epigenetic alteration and warrants evaluation as an adjunctive signal for early screening.

Humans↗
PubMed2026

Cholesterol dysregulation in APOE4 astrocytes promotes α-synuclein pathology in miBrains.

The pathological hallmarks of neurodegeneration are the aberrant post-translational modification and aggregation of proteins. Genetic factors, like APOE4, increase the prevalence and severity of tau, amyloid, and α-synuclein pathologies. However, the human brain is largely inaccessible during this process, limiting mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a human brain-like tissue ("miBrain"). Single-nucleus RNA sequencing of miBrains confirmed the presence of diverse cell populations and revealed transcriptional responses to α-synuclein pathology. Like the human brain, pathogenic α-synuclein is increased in APOE4/4 miBrains. Combinatorial experiments revealed that endolysosomal dysfunction caused by cholesterol accumulation in APOE4/4 astrocytes impairs the degradation of soluble α-synuclein leading to a pathogenic transformation that seeds α-synuclein inclusions in neurons. Collectively, this study establishes a robust model for investigating protein inclusions in human iPSC-derived brain tissue and highlights the role of astrocytes and cholesterol in APOE4-mediated pathologies.

alpha-Synuclein↗
PubMed2026

TogoPhosTAC as a delivery-ready platform for targeted protein dephosphorylation.

Phosphorylation-targeting chimeras (PhosTACs) enable targeted protein dephosphorylation by recruiting phosphatases through induced proximity. However, the direct recruitment of phosphatase subunits or holoenzymes with small molecules remains challenging, as suitable ligands are scarce and often compromise enzymatic activity or cellular function. Here, we present togoPhosTAC, a hybrid modality that integrates a small-molecule PhosTAC, an engineered FKBP12F36V-phosphatase, and a lipid nanoparticle delivery system. This strategy allows delivery of preassembled PhosTAC-FKBP12F36V-phosphatase complexes or PhosTAC-phosphatase mRNA, enabling rapid and efficient intracellular dephosphorylation. We demonstrate that togoPhosTAC can selectively dephosphorylate EGFR, α-synuclein, and tau in biological contexts, providing a versatile strategy that circumvents the need for genetically engineered phosphatases. We also find togoPhosTAC further enhances tau dephosphorylation as well as its disaggregation in cellulo. Importantly, intrahippocampal or intranasal delivery of togoPhosTAC in PS19 tau transgenic male mice leads to a marked reduction in pathological tau phosphorylation across multiple sites (Ser202, Thr205, Thr231, Ser396, and Ser404), decreases pathological tau burden in related brain regions, and improves Alzheimer's disease-related behavioral deficits. Together, these findings establish a versatile and generalizable approach for precise protein dephosphorylation in disease-relevant systems, overcoming key limitations in phosphatase-recruiting drug discovery.

Animals↗
PubMed2026

In Vivo Screen of Parkinson's Disease GWAS Risk Genes Identifies ARIH2 as a Novel Regulator of α-Synuclein Toxicity in Dopaminergic Neurons.

Parkinson's disease (PD) is a late-onset neurodegenerative disease characterized by preferential degeneration of midbrain dopaminergic neurons and α-synuclein-containing Lewy bodies that are found in both familial and sporadic forms. Genome-wide association studies (GWAS) have identified many loci associated with risk of sporadic PD, but their role in PD pathogenesis remains largely unknown. We screened a subset of GWAS genes in Caenorhabditis elegans (C. elegans) as potential modulators of α-synuclein-mediated degeneration of dopaminergic neurons. Loss of ari-2 (human ARIH2), an E3 ubiquitin ligase, was identified as the strongest suppressor of dopaminergic neurodegeneration in C. elegans. Unbiased proteomics analysis in human-induced pluripotent stem cell-derived dopaminergic neurons revealed novel substrates of ARIH2 including TPPP3, a regulator of microtubule dynamics. Importantly, TPPP3 was required for ARIH2's effects on α-synuclein-induced dopaminergic neurodegeneration. Our studies reveal an unexpected genetic interaction between two PD-linked genes, α-synuclein and ARIH2, and suggest that inhibition of ARIH2's enzymatic activity may serve as a potential therapeutic approach in PD.

Animals↗