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bioRxiv · 10.1101/2023.07.31.551324

CCT and Cullin1 regulate the TORC1 pathway to promote dendritic arborization in health and disease.

Lottes, E. N.·Ciger, F. H.·Bhattacharjee, S.·Timmins-Wilde, E. A.·Tete, B.·Tran, T.·Matta, J.·Patel, A. A.·Cox, D. N.
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Abstract

The development of cell-type-specific dendritic arbors is integral to the proper functioning of neurons within their circuit networks. In this study, we examine the regulatory relationship between the cytosolic chaperonin CCT, key insulin pathway genes, and an E3 ubiquitin ligase (Cullin1) in homeostatic dendritic development. CCT loss of function (LOF) results in dendritic hypotrophy in Drosophila Class IV (CIV) multidendritic larval sensory neurons, and CCT has recently been shown to fold components of the TOR (Target of Rapamycin) complex 1 (TORC1), in vitro. Through targeted genetic manipulations, we have confirmed that LOF of CCT and the TORC1 pathway reduces dendritic complexity, while overexpression of key TORC1 pathway genes increases dendritic complexity in CIV neurons. Both CCT and TORC1 LOF significantly reduce microtubule (MT) stability. CCT has been previously implicated in regulating proteinopathic aggregation, thus we examined CIV dendritic development in disease conditions as well. Expression of mutant Huntingtin leads to dendritic hypotrophy in a repeat-length-dependent manner, which can be rescued by TORC1 disinhibition via Cullin1 LOF. Together, our data suggest that Cullin1 and CCT influence dendritic arborization through regulation of TORC1 in both health and disease. SIGNIFICANCEThe insulin pathway has become an increasingly attractive target for researchers interested in understanding the intersection of metabolism and brain health. We have found connections between the insulin pathway and cytosolic protein maintenance in the development of neuronal dendrites. These pathways converge on the dendritic cytoskeleton, particularly microtubules. Neurons expressing mutant Huntingtin also show defects in dendritic development and the underlying cytoskeleton, and we find that disinhibition of the insulin pathway can rescue dendritic hypotrophy in these neurons. This work advances our understanding of the molecular interactions between the insulin pathway and neuronal development in both health and Huntingtons Disease conditions.

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Lottes, E. N., Ciger, F. H., Bhattacharjee, S., Timmins-Wilde, E. A., Tete, B., Tran, T., Matta, J., Patel, A. A., Cox, D. N.. 2023-08-02. CCT and Cullin1 regulate the TORC1 pathway to promote dendritic arborization in health and disease.. https://doi.org/10.1101/2023.07.31.551324

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