Biology subjects

Pletnikova, O.

Publications and source records attributed to Pletnikova, O..

10 recordsLinked to original sources

bioRxiv2025

Repeat associated non-AUG translation as a common mechanism for the polyGln ataxias

Determining if repeat associated non-AUG (RAN) proteins contribute to the CAG polyGln-encoding spinocerebellar ataxias (CAG-SCAs) is critical for understanding mechanisms and developing therapies for these diseases. Immunohistochemistry using antibodies against polySer and polyLeu repeats and locus specific C-terminal regions show sense polySer (AGC frame) and antisense polyLeu (CUG frame) RAN proteins accumulate in affected grey and white-matter brain regions, throughout the cerebellum and pons, in SCA1, SCA2, SCA3, SCA6, and SCA7 autopsy brains. Cerebellar white matter regions with prominent polySer and polyLeu but minimal polyGln aggregates show demyelination, white matter loss, and activated microglia. In SCA3 mice, RAN proteins accumulate in an age-dependent manner. In neural cells, polySer and polyLeu RAN proteins are toxic and cause autophagic dysfunction. In cells, the FDA-approved drug metformin decreases RAN protein levels and reduces toxicity. Taken together, these data identify sense and antisense RAN proteins as a common molecular mechanism shared by the CAG-SCAs.

neuroscience↗

bioRxiv2025

UNC-45A Drives ATP-Independent Microtubule Destabilization via Defect Recognition and Repair Inhibition Contributing to Neurite Dystrophy

UNC-45A is the only known ATP-independent microtubule severing protein. Using in vitro reconstitution and TIRF microscopy, we show that, unlike canonical severing enzymes such as katanin, spastin, and fidgetin, which hydrolyze ATP to remove tubulin dimers and promote lattice repair, UNC-45A selectively binds to pre-existing microtubule defects and inhibits GTP-tubulin incorporation. This mechanism prevents the formation of stabilized hot spots that typically protect microtubules from disassembly, resulting in persistent lattice damage and net microtubule loss, even in the presence of physiological levels of free GTP-tubulin. We further demonstrate that UNC-45A localizes near amyloid deposits in both mouse models and human cases of Alzheimers disease (AD). In cultured neurons, UNC-45A accumulates in axonal swellings--regions of pronounced microtubule disruption and experimental surrogates for dystrophic neurites in AD--and exacerbates their size and number, particularly under conditions mimicking microtubule damage. Notably, this is the first report of a microtubule severing protein that both localizes near amyloid plaques in tissue and accumulates in neurite swellings in cultured neurons, where it modulates their pathology. Together, our findings establish the mechanism of ATP-independent, damage-responsive severing pathway that couple defects recognition to repair inhibition, defining a new paradigm in microtubule quality control with broad implications for cytoskeletal integrity and remodeling in health and disease.

cell biology↗

bioRxiv2025

Dissecting the molecular landscape of Parkinson's disease and Parkinson's disease dementia using highly efficient snRNA-seq (HIF-snRNA-seq)

This study presents a transcriptomic analysis of the cingulate cortex (CING) in Parkinsons disease (PD) and Parkinsons disease dementia (PDD) using a High-efficiency single-nucleus RNA sequencing (HiF-snRNA-seq) protocol optimized for post-mortem brain samples. RNA quality prediction, poly-A tailing, and dCas9-targeted depletion enabled analysis of 77 high-quality samples from 240 cases, yielding over 2 million nuclei classified into seven major cell types. Disease conditions revealed altered astrocyte and microglia proportions, implicating their roles in neuroinflammation. Differential expression analysis identified unique and shared genes across PD and PDD, linked to synaptic remodeling, stress responses, and inflammation. Stage-specific analysis uncovered tau-dependent early-stage genes and inflammation-associated late-stage genes. This study highlights the CINGs central role in PD and PDD pathophysiology, offering insights into disease mechanisms and identifying candidate genes and pathways for therapeutic and biomarker development.

genomics↗

bioRxiv2023

Towards a human brain EV atlas: Characteristics of EVs from different brain regions, including small RNA and protein profiles

Extracellular vesicles (EVs) are released from different cell types in the central nervous system (CNS) and play roles in regulating physiological and pathological functions. Although brain-derived EVs (bdEVs) have been successfully collected from brain tissue, there is not yet a "bdEV atlas" of EVs from different brain regions. To address this gap, we separated EVs from eight anatomical brain regions of a single individual and subsequently characterized them by count, size, morphology, and protein and RNA content. The greatest particle yield was from cerebellum, while the fewest particles were recovered from the orbitofrontal, postcentral gyrus, and thalamus regions. EV surface phenotyping indicated that CD81 and CD9 were more abundant than CD63 for all regions. Cell-enriched surface markers varied between brain regions. For example, putative neuronal markers NCAM, CD271, and NRCAM were more abundant in medulla, cerebellum, and occipital regions, respectively. These findings, while restricted to tissues from a single individual, suggest that additional studies are merited to lend more insight into the links between EV heterogeneity and function in the CNS.

neuroscience↗

bioRxiv2022

Surface phenotyping and quantitative proteomics reveal differentially enriched proteins of brain-derived extracellular vesicles in Parkinson's disease

Extracellular vesicles (EVs) are produced by all cell types and are found in all tissues and biofluids. EV proteins, nucleic acids, and lipids are a "nano-snapshot" of the parent cell that may be used for novel diagnostics of various diseases, including neurodegenerative disorders. Currently, diagnosis of the most common neurodegenerative movement disorder, Parkinsons disease (PD), relies on manifestations of late-stage progression, which may furthermore associate with other neurodegenerative diseases such as progressive supranuclear palsy (PSP). Here, we profiled surface markers and other protein contents of brain-derived extracellular vesicles (bd-EVs) from PD (n= 24), PSP (n=25) and control (n=24). bdEVs displayed tetraspanins and certain microglia, astrocyte, and neuron markers, while quantitative proteomics revealed enrichment of several proteins in PD vs. control and/or PSP, including clathrin heavy chain 1 and 14-3-3 protein gamma. This characterization of EVs in the source tissue provides insights into local dynamics as well as biomarker candidates for investigation in peripheral fluids.

neuroscience↗

bioRxiv2021

APOE ε4 allele advances the age-dependent decline of amyloid β clearance in the human cortex

IntroductionOur previous study indicated that the pericapillary clearance of amyloid {beta} (A{beta}) declines with age in APOE 3/3 subjects. Here, we examine whether the APOE {varepsilon}4 allele has an impact on this age-related decline. MethodsWe examined 69 autopsy brains of APOE {varepsilon}3/{varepsilon}4 or APOE {varepsilon}3/{varepsilon}3 individuals (30-65 years) for the immunohistochemical localization of intracellular, extracellular, and pericapillary A{beta} in the cerebral cortex. ResultsIn APOE {varepsilon}3/{varepsilon}4 individuals, the percentage of A{beta} positive pericapillary spaces began to decrease (p=0.030), and the number of extracellular A{beta} particles increased in the early 30s (p=0.0008). Those average values were significantly lower (p<0.0001) and higher (p<0.0001), respectively, compared to APOE {varepsilon}3/{varepsilon}3 individuals. DiscussionOur observations indicate that APOE {varepsilon}4 allele advances by one decade at the onset of age-related decline in A{beta} glymphatic clearance. This finding supports early clinical intervention and stratification by APOE genotype to prevent A{beta} deposition and AD progression.

pathology↗

bioRxiv2020

Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy

The genetic basis of variation in the rate of disease progression of primary tauopathies has not been determined. In two independent progressive supranuclear palsy cohorts, we show that common variation at the LRRK2 locus determines survival from motor symptom onset to death, possibly through regulation of gene expression. This links together genetic risk in alpha-synuclein and tau disorders, and suggests that modulation of proteostasis and neuro-inflammation by LRRK2 inhibitors may have a therapeutic role across disorders.

genetics↗

bioRxiv2019

Mutations in the SPTLC1 gene are a cause of amyotrophic lateral sclerosis that may be amenable to serine supplementation

Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of childhood motor disorder with a heterogeneous clinical presentation. The underlying causes of this condition are poorly understood, hindering the development of effective therapies. In a whole-exome sequencing trio-family study of three unrelated juvenile patients diagnosed with ALS and failure to thrive, we identified de-novo mutations in SPTLC1 (p.Ala20Ser in two patients and p.Ser331Tyr) not present in their healthy parents or siblings. SPTLC1 encodes a subunit of the serine palmitoyltransferase complex, a key enzyme in sphingolipid biosynthesis. Mutations in this gene are known to cause hereditary sensory autonomic neuropathy, type 1A, with a characteristic increase in plasma levels of neurotoxic deoxymethyl-sphinganine. We found an increase of this metabolite in one of our patients carrying the p.Ala20Ser mutation. Treatment of one of the patients with high dose, oral L-serine led to an increase in body weight, suggesting that serine supplementation may be beneficial among patients carrying mutations in this gene.

genetics↗

bioRxiv2019

Discovery of several thousand highly diverse circular DNA viruses

Although it is suspected that there are millions of distinct viral species, fewer than 9,000 are catalogued in GenBanks RefSeq database. We selectively enriched for and amplified the genomes of circular DNA viruses in over 70 animal samples, ranging from cultured soil nematodes to human tissue specimens. A bioinformatics pipeline, Cenote-Taker, was developed to automatically annotate over 2,500 circular genomes in a GenBank-compliant format. The new genomes belong to dozens of established and emerging viral families. Some appear to be the result of previously undescribed recombination events between ssDNA viruses and ssRNA viruses. In addition, hundreds of circular DNA elements that do not encode any discernable similarities to previously characterized sequences were identified. To characterize these "dark matter" sequences, we used an artificial neural network to identify candidate viral capsid proteins, several of which formed virus-like particles when expressed in culture. These data further the understanding of viral sequence diversity and allow for high throughput documentation of the virosphere.

microbiology↗

bioRxiv2018

Heritability and genetic variance of dementia with Lewy bodies

Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinsons disease (PD) or Alzheimers disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants.

neuroscience↗