Biology subjects

Altay, M. F.

Publications and source records attributed to Altay, M. F..

4 recordsLinked to original sources

bioRxiv2026

SysNDD: A Systematic Database for Neurodevelopmental Disorders

Neurodevelopmental disorders (NDDs) are clinically and genetically heterogeneous, and evidence linking additional genes to disease evolves rapidly. We developed SysNDD, an open-access, expert-curated resource that represents distinct gene-inheritance-disease associations as entities with standardized confidence, phenotype, and variant annotations. Each entity retains its curation history, so its evidence category can change as evidence accumulates. Currently, SysNDD contains 4,275 entities curated from 4,932 publications. Of these, 3,758 entities involving 3,271 genes describe NDDs; the remainder record non-NDD disorders, nearly all linked to NDD-associated genes, included for completeness. Regarding NDD evidence categories, 1,838 genes are Definitive, 179 Moderate, 1,248 Limited, and 6 Refuted. The entity model captures inheritance-specific disorders, including 220 genes with both autosomal dominant and autosomal recessive NDD associations. Comparison with seven other NDD gene resources showed complementary coverage, and evidence categories largely agreed with those of ClinGen, Gene2Phenotype, and PanelApp for shared gene-disease pairs. NDD genes formed distinct molecular modules, whereas associated disorders formed broad, overlapping phenotype groups that corresponded to those modules only selectively. SysNDD provides a continuously maintained, programmatically accessible framework for gene-disease evidence assessment, inheritance-aware interpretation, and systematic NDD research.

genetics↗

bioRxiv2024

Dissecting the differential role of C-terminal truncations in the regulation of aSyn pathology formation and the biogenesis of Lewy bodies

Alpha-synuclein (aSyn) post-translational modifications (PTMs), particularly phosphorylation at serine 129 and C-terminal truncations, are highly enriched in Lewy bodies (LBs), Lewy neurites, and other types of aSyn pathological aggregates in the brain of patients with Parkinsons disease (PD) and other synucleinopathies. However, our knowledge about the precise role of PTMs in regulating the different stages of pathology formation, neurodegeneration, and aSyn pathology spreading remains incomplete. In this work, we applied a systematic approach to address this knowledge gap with an emphasis on mapping and elucidating the role of post-fibrillization C-terminal aSyn truncations in regulating the uptake, processing, seeding activity, and formation of LB-like inclusions and maturations in a well-established neuronal seeding model that recapitulates all the stages leading to LB formation and neurodegeneration. Our work shows that C-terminal cleavage of aSyn fibrils at multiple sites is a conserved process that occurs rapidly after and during the formation of intracellular LB-like aSyn inclusions in all neuronal seeding models. Interestingly, blocking the cleavage of internalized fibrils does not influence their seeding activity, whereas inhibiting the enzymes that regulate the cleavage of newly formed fibrils (e.g., calpains 1 and 2) significantly alters the formation of LB-like inclusions. We also show that C-terminal truncations, in combination with other PTMs, play a crucial role in regulating the interactome and remodeling of newly formed aSyn fibrils, including their shortening, lateral association, and packing during LB formation and maturation. Altogether, our results demonstrate that post-fibrillization C-terminal truncations have a differential role at different stages of aSyn aggregation and pathology formation. These insights, combined with the abundance of truncated aSyn species in LBs, have significant implications in understanding aSyn pathological diversity and developing therapeutic strategies targeting the C-terminus of aSyn or its proteolytic processing.

neuroscience↗

bioRxiv2022

Prominent astrocytic alpha-synuclein pathology with unique post-translational modification signatures unveiled across Lewy body disorders

Alpha-synuclein (aSyn) is a pre-synaptic monomeric protein that can form aggregates in neurons in Parkinsons disease (PD), Parkinsons disease with dementia (PDD) and dementia with Lewy bodies (DLB), and in oligodendrocytes in multiple system atrophy (MSA). Although the accumulation of aSyn in astrocytes has previously been described in PD, PDD and DLB, the biochemical properties of aSyn in this type of pathology and its topographical distribution have not been studied in detail. Here, we present a systematic investigation of aSyn astrocytic pathology, using an expanded toolset of antibodies covering the entire sequence and known post-translational modifications (PTMs) of aSyn in Lewy body (LB) disorders, including sporadic PD, PDD, DLB, familial PD with SNCA G51D mutation and SNCA duplication, and in MSA. Astrocytic aSyn was mainly detected in the limbic cortical regions of LB disorders, but were absent in key pathological regions of MSA. These astrocytic aSyn accumulations were detected only with aSyn antibodies against the mid N-terminal and non-amyloid component (NAC) regions covering aSyn residues 34-99. The astroglial accumulations were negative to canonical aSyn aggregation markers, including p62, ubiquitin and aSyn pS129, but positive for phosphorylated and nitrated forms of aSyn at Tyrosine 39 (Y39), and mostly not resistant to proteinase K. Our findings suggest that astrocytic aSyn accumulations are a major part of aSyn pathology in LB disorders, and possess a distinct sequence and PTM signature that is characterized by both N- and C-terminal truncations and modifications at Y39. To the best of our knowledge, this is the first description of aSyn accumulation made solely from N- and C-terminally cleaved aSyn species and the first report demonstrating that astrocytic aSyn exists as a mixture of Y39 phosphorylated and nitrated species. These observations underscore the critical importance of systematic characterization of aSyn accumulation in different cell types as a necessary step to capturing the diversity of aSyn species and pathology in the brain. Our findings combined with further studies on the role of astrocytic pathology in the progression of LB disorders can pave the way towards identifying novel disease mechanisms and therapeutic targets.

neuroscience↗

bioRxiv2022

Development and validation of an expanded antibody toolset that captures alpha-synuclein pathological diversity in Lewy body diseases

The abnormal aggregation and accumulation of alpha-synuclein (aSyn) in the brain is a defining hallmark of synucleinopathies. Different aSyn conformations and post-translationally modified forms accumulate in pathological inclusions and vary in abundance across synucleinopathies. Relying on antibodies that have not been assessed for their ability to capture the diversity of aSyn species may not provide an accurate estimation of aSyn pathology in human brains or disease models. To address this challenge, we developed and characterised an expanded antibody panel that targets different sequences and post-translational modifications along the length of aSyn and recognises all three aSyn conformations (monomeric, oligomeric, fibrillar). Next, we profiled aSyn pathology across sporadic and familial Lewy body diseases (LBDs) and reveal heterogeneously modified aSyn pathologies rich in Serine 129 phosphorylation but also in Tyrosine 39 nitration and N- and C-terminal tyrosine phosphorylations, scattered to neurons and glia. We also show that aSyn may become hyperphosphorylated during the aggregation and inclusion maturation processes in neuronal and animal models of aSyn aggregation and spreading. The antibody validation pipeline we describe here paves the way for more systematic investigations of aSyn pathological diversity in the human brain and peripheral tissues, and in cellular and animal models of synucleinopathies.

neuroscience↗