Biology subjects

BK, B.

Publications and source records attributed to BK, B..

3 recordsLinked to original sources

bioRxiv2023

DystoGen Compendium: A comprehensive resource of ACMG annotated movement disorder associated genetic variants

PurposeIn recent years, the advent of high throughput sequencing techniques has led to the identification of a number of genetic variants across different genes that are associated with movement disorders. However, the under-appreciation of the variant spectrum in movement disorders and the lack of consolidated and systematic evidence-based annotation of these variants has long undermined the true potential of genomic approaches to expedite precision medicine. MethodsWe manually curated the genetic variants from a panel of 118 genes that have been associated with monogenic causes of movement disorders and systematically annotated them according to ACMG & AMP (American College of Medical Genetics and the Association of Molecular Pathologists) guidelines. ResultsData integration after systematic classification of variants according to ACMG & AMP guidelines showed 5118 pathogenic/likely pathogenic variants accounting for 18.03% of the total unique variants being annotated. This data and annotations are available in a comprehensive online compendium DystoGen. ConclusionTo the best of our knowledge, this is the most comprehensive compendium of genetic variants in movement disorders annotated as per the ACMG & AMP guidelines for pathogenicity. The compendium indexes 28377 variants along with a wide array of information including the geographical origin of the variant, global distribution, and population allele frequency. The resource has been made available in the URL https://clingen.igib.res.in/dystogen/.

bioinformatics↗

bioRxiv2022

Inhibition of hyperactive cyclin dependent kinase 5/p25 is protective in the 6-hydroxydopamine model of Parkinson's disease

BackgroundCyclin-dependent kinase 5 (CDK5) is a multifunctional enzyme involved in neuronal development, maturation and survival. CDK5 activity is tightly regulated by association with regulatory proteins p35 and p39. Upon neuronal insults, increased intracellular calcium activates calpain, cleaving p35 into p25, which has a higher affinity for CDK5. p25 hyperactivates CDK5, initiating apoptotic cascades that lead to significant dopaminergic (DAergic) loss that can leads to neurodegenerative disorders, such as Parkinsons disease (PD). ObjectiveThis study investigates hyperactivation of CDK5/p25 in the 6-hydroxydopamine (6-OHDA) rat model of PD and specific inhibition of CDK5/p25 by truncated peptide 5 (TP5). TP5 was investigated for amelioration of 6-OHDA induced behaviour impairments and significant protection of dopamine neurons through tyrosine hydroxylase (TH). Methods6-OHDA induced motor impairments and reduced TH. Motor assessments included locomotor activity, beam transversal, fixed speed rotarod and amphetamine-induced rotations. Immunohistochemistry investigated DAergic neurodegeneration using TH levels and immunoprecipitation and assay investigated CDK5 activity. ResultsPre-administration of TP5 maintained locomotor activity, preserved beam transversal scores, protected motor coordination and attenuated amphetamine induced rotations in 6-OHDA lesioned rats, all indicative of neuroprotection by TP5. 6-OHDA without pretreatment of TP increased CDK5 activation. CDK5 activity in TP5+6-OHDA animals was not significantly different from artificial cerebrospinal fluid (aCSF) treated sham surgery controls. Immunohistochemistry revealed significant TH protection within the substantia nigra (SN) of TP5 pretreated animals. Conclusions6-OHDA increases CDK5 activity. Hyperactive CDK5/p25 inhibition in the 6-OHDA model has neuroprotective capability, protecting against the development of a toxin-based induction of PD-like motor phenotypes and pathology. This supports CDK5/p25 specific inhibition as a target for further neuroprotective therapeutic development.

pharmacology and toxicology↗

bioRxiv2021

CDK5 mediated phosphorylation of cytosolic phospholipase A2 regulates its activity and neuroinflammation in Parkinsons Disease

Hyperactivation of cyclin-dependent kinase 5 (CDK5) by p25, contributes to neuroinflammation causing neurodegeneration in Parkinsons Disease (PD) and Alzheimer diseases (AD). However, the mechanism by which CDK5 induces neuroinflammation in the PD brain is largely unexplored. Here, we show that CDK5 phosphorylates cytosolic phospholipase A2 (cPLA2) at Thr-268 and Ser-505 sites lead to its activation and generation of eicosanoid products. Mutational studies using site-directed mutagenesis and molecular simulations show that the architecture of the protein changes upon each single-point mutation. Interestingly, double-mutations also led to severe decline in the activity of cPLA2 and disruption of its translocation to the plasma membrane. Further, the brain lysates of transgenic PD mouse models show hyperactivation of CDK5 resulting in enhanced phosphorylation of Thr-268 and Ser-505 of cPLA2 and its heightened activity confirming the findings observed in the cell culture model of PD. These phosphorylation sites of cPLA2 and CDK5 could be explored as the future therapeutic targets against neuroinflammation in PD. Further, conjoint transcriptomic analysis of the publicly available human PD datasets strengthens the hypothesis that genes of the arachidonic acid, prostaglandin synthesis and inflammatory pathways are significantly upregulated in case of the PD patients as compared to that of healthy controls.

neuroscience↗