Biology subjects

Puri, S.

Publications and source records attributed to Puri, S..

4 recordsLinked to original sources

bioRxiv2023

GSK3β phosphorylation catalyzes the aggregation of Tau into Alzheimer's disease-like amyloid strain

The pathological deposition of proteins is a hallmark of several devastating neurodegenerative diseases. These pathological deposits comprise aggregates of proteins that adopt distinct structures named strains. However, the molecular factors responsible for the formation of distinct aggregate strains are unknown. Here we show that the serine/threonine kinase GSK3{beta} catalyzes the aggregation of the protein tau into an Alzheimers disease-like amyloid strain. We demonstrate that phosphorylation by GSK3{beta}, but not by several other kinases, promotes the aggregation of full-length tau through enhanced phase separation into gel-like condensate structures. Cryo-electron microscopy further reveals that the amyloid fibrils formed by GSK3{beta}-phosphorylated tau adopt a fold comparable to that of paired helical filaments isolated from the brains of AD patients. Our results elucidate the intricate relationship between post-translational modification and the formation of tau strains in neurodegenerative diseases.

biophysics↗

bioRxiv2023

Proximity labeling reveals dynamic changes in the SQSTM1 protein network

Sequestosome1 (SQSTM1) is an autophagy receptor that mediates degradation of intracellular cargo, including protein aggregates, through multiple protein interactions. These interactions form the SQSTM1 protein network, and these interactions are mediated by SQSTM1 functional interaction domains, which include LIR, PB1, UBA and KIR. Technological advances in cell biology continue to expand our knowledge of the SQSTM1 protein network and of the relationship of the actions of the SQSTM1 protein network in cellular physiology and disease states. Here we apply proximity profile labeling to investigate the SQSTM1 protein interaction network by fusing TurboID with the human protein SQSTM1 (TurboID::SQSTM1). This chimeric protein displayed well-established SQSTM1 features including production of SQSTM1 intracellular bodies, binding to known SQSTM1 interacting partners, and capture of novel SQSTM1 protein interactors. Strikingly, aggregated tau protein altered the protein interaction network of SQSTM1 to include many stress-associated proteins. We demonstrate the importance of the PB1 and/or UBA domains for binding network members, including the K18 domain of tau. Overall, our work reveals the dynamic landscape of the SQSTM1 protein network and offers a resource to study SQSTM1 function in cellular physiology and disease state.

cell biology↗

bioRxiv2022

Identification of circRNAs linked to Alzheimer's disease and related dementias

We conducted a circular-transcriptome-wide analysis and examined circRNA expression patterns associated with AD and clinical and neuropathological AD severity measures in human hippocampus and cortex brain regions. We validated prior studies of circRNA in AD cortex, and demonstrate novel patterns of expression in the AD hippocampus. We also examined circRNA expression across multiple types of dementia and show that circRNA expression differs by dementia subtype. We demonstrate robust circRNA expression in human neuronal precursor cells (NPCs). Then, using NPCs to study qPCR validated circRNA, we show that exposure to oligomeric tau elicits downregulation of circRNA similar to that observed in AD brain. These data identify circRNA that are changed with AD, and suggest that treating neuronal cells with oligomeric tau can recapitulate some of these changes.

molecular biology↗

bioRxiv2022

Corynebacterium matruchotii fitness enhancement of adjacent streptococci by multiple mechanisms

Polymicrobial biofilms are present in many environments particularly in the human oral cavity where they can prevent or facilitate the onset of disease. While recent advances have provided a clear picture of both the constituents and their biogeographical arrangement, it is still unclear what mechanisms of interaction occur between individual species in close proximity within these communities. In this study we investigated two mechanisms of interaction between the highly abundant supragingival plaque (SUPP) commensal Corynebacterium matruchotii and Streptococcus mitis which are directly adjacent in vivo. We discovered that C. matruchotii enhanced the fitness of streptococci dependent on its ability to detoxify streptococcal-produced hydrogen peroxide and its ability to oxidize lactate also produced by streptococci. We demonstrate that the fitness of adjacent streptococci was linked to that of C. matruchotii and that these mechanisms support the previously described "corncob" arrangement between these species but that this is favorable only in aerobic conditions. Further we utilized scanning electrochemical microscopy (SECM) to quantify lactate production and consumption between individual bacterial cells for the 1st time, revealing that lactate oxidation provides a fitness benefit to S. mitis and not pH mitigation. This study describes mechanistic interactions between two highly abundant human commensals that can explain their observed in vivo spatial arrangements and suggest a way by which they may help preserve a healthy oral bacterial community.

microbiology↗