Biology subjects

Deo, A.

Publications and source records attributed to Deo, A..

3 recordsLinked to original sources

bioRxiv2023

Identification of two novel DnaJ chaperone family proteins as modifiers of Huntingtin aggregates

Huntingtons disease (HD) is a rare neurodegenerative disease. It is caused due to aggregation of Huntingtin (HTT) protein containing Q repeats more than 40. Similar protein aggregation is also a hallmark of several other neurodegenerative diseases related to loss of cognitive function. In search of modifiers of HTT aggregation, we have screened putative chaperone proteins from Drosophila in both fly and yeast model of HD. DnaJ chaperones were screened by evaluating HTT protein aggregation related phenotypes using growth assays for studying the growth rate of the cells, imaging studies, and gel-based approaches like semi-denaturing detergent agarose gel electrophoresis (SDD-AGE). Our screening led us to categorize several proteins as suppressors and enhancers of the HTT associated phenotypes. Out of the 40 chaperones and co-chaperones, two chaperones that came up strikingly were CG5001 and P58IPK. Protein aggregation was found to be reduced in both S2 cells and Drosophila transgenic lines with HTT103Q in presence of these class of chaperones. As these DnaJ chaperones have protein sequence similarity across species, these might be used as possible tools to combat the effects of neurodegenerative diseases, as evidenced specifically in Huntingtons disease and Amyotrophic Lateral Sclerosis (ALS).

genetics↗

bioRxiv2022

Mrj an Hsp40 family chaperone regulates oligomerization of Orb2 and long-term memory

Orb2 the Drosophila homolog of Cytoplasmic polyadenylation element binding protein (CPEB) forms prion-like oligomers. These oligomers consist of Orb2A and Orb2B isoforms and their formation are dependent on the oligomerization of the Orb2A isoform. Drosophila with a mutation diminishing Orb2As prion-like oligomerization forms long-term memory but fails to maintain it over time. Since, this prion-like oligomerization of Orb2A plays a crucial role in the maintenance of memory, here we aim to find what regulates this oligomerization. In an immunoprecipitation-based screen, we identify interactors of Orb2A in the Hsp40 and Hsp70 families of proteins. Amongst these, we find an Hsp40 family protein Mrj as a regulator of the conversion of Orb2A to its prion-like form. Mrj interacts with Hsp70 proteins and acts as a chaperone by interfering with the aggregation of pathogenic Huntingtin. Unlike its mammalian homolog, we find Drosophila Mrj is neither an essential gene nor causes any gross neurodevelopmental defect. We observe a loss of Mrj results in a reduction in Orb2 oligomers. Further, the knockdown of Mrj in the mushroom body neurons results in a deficit in long-term memory. Our work implicates a chaperone Mrj in mechanisms of memory regulation through controlling the oligomerization of Orb2A and its association with the translating polysomes.

neuroscience↗

bioRxiv2020

Human brain organoids reveal accelerated development of cortical neuron classes as a shared feature of autism risk genes

Genetic risk for autism spectrum disorder (ASD) has been associated with hundreds of genes spanning a wide range of biological functions. The phenotypic alterations in the human brain resulting from mutations in ASD risk genes remain unclear, and the level at which these alterations converge on shared disease pathology is poorly understood. Here, we leveraged reproducible organoid models of the human cerebral cortex to identify cell type-specific developmental abnormalities associated with haploinsufficiency in three ASD risk genes, SUV420H1 (KMT5B), PTEN, and CHD8. We performed comprehensive single-cell RNA-sequencing (scRNA-seq) of over 400,000 cells, and proteomic analysis on individual organoids sampled at different developmental stages to investigate phenotypic convergence among these genes. We find that within a defined period of early cortical development, each of the three mutations demonstrates accelerated development of cortical neurons. Notably, they do so by affecting different neuronal populations: excitatory deep layer (SUV420H1) and callosal (PTEN) neurons, and inhibitory interneurons (CHD8). This work shows that haploinsufficiency in ASD risk genes converge on early developmental defects in the generation of neurons of the cortical microcircuit.

developmental biology↗