Biology subjects

Van Pelt, K. M.

Publications and source records attributed to Van Pelt, K. M..

3 recordsLinked to original sources

bioRxiv2026

Ficd loss rescues motor impairments and reverses oligodendrocyte maturation deficits in a mouse model of spinocerebellar ataxia type 3

Spinocerebellar ataxia type 3 (SCA3) is an inherited, fatal neurodegenerative disease caused by a pathological CAG repeat expansion in the ATXN3 gene, resulting in the selective degeneration of vulnerable neuronal populations. Recent work has identified impairments in oligodendrocyte maturation as a novel and robust feature of SCA3 pathogenesis. Oligodendrocytes synthesize myelin structural components through the endoplasmic reticulum (ER), rendering this organelle essential for white matter integrity. Despite this, the role of ER function in SCA3 remains unclear. In this study, we show that loss of FICD-mediated AMPylation, a post-translational modification regulating the ER-resident HSP70 chaperone, BiP, rescues motor impairments in a transgenic SCA3 mouse model. Ficd-/- SCA3 mice exhibit significantly reduced levels of nuclear ATXN3 in vulnerable brain regions, while Ficd+/+ littermates show an increased burden of AMPylated BiP in the spinal cord, identifying aberrant AMPylation as a novel contributor of SCA3 pathology. Using unbiased proteomics, we demonstrate that Ficd deletion mitigates the pathological decrease in myelin structural proteins and oligodendrocyte maturation factors, restoring levels of mature, myelinating oligodendrocytes. In parallel, we show that Ficd activates SREBP2-dependent cholesterol biosynthesis to support myelination. Taken as a whole, these findings posit ER homeostasis as a critical driver of oligodendrocyte pathology and identify FICD as a novel target for alleviating non-neuronal toxicity in SCA3.

molecular biology↗

bioRxiv2025

Functionally diversified BiP orthologs control body growth, reproduction, stress resistance, aging, and ER-Phagy in Caenorhabditis elegans.

Cellular systems that govern protein folding rely on a delicate balance of functional redundancy and diversification to maintain protein homeostasis (proteostasis). Here, we use Caenorhabditis elegans to demonstrate how both overlapping and divergent activities of two homologous endoplasmic reticulum (ER)-resident HSP70 family chaperones, HSP-3 and HSP-4, orchestrate ER proteostasis and contribute to organismal physiology. We identify tissue-, age-, and stress-specific protein expression patterns and find both redundant and distinct functions for HSP-3 and HSP-4 in ER stress resistance, reproduction, and body size regulation. We show that only HSP-3 overexpression is sufficient to improve longevity and that loss of HSP-3 or HSP-4 during distinct stages of the worm cycle or specific tissues have opposing effects on worm lifespan. Furthermore, we find that loss of HSP-4, but not HSP-3, improves tolerance to protein aggregation induced-stress by activating ER-Phagy through the engagement of IRE-1 and the putative ER-Phagy receptor, C18E9.2. Mechanistically, we show that de-repression of IRE-1 via HSP-4 dissociation allows for direct inhibition of C18E9.2- mediated ER-Phagy and demonstrate that a conserved orthologous mechanism involving the respective human orthologs, BiP, Sec-62, and IRE-1, contributes to ER proteostasis regulation in human cells. Taken as a whole, our study demonstrates that functional diversification of orthologous proteins within a single organelle is an efficient mechanism to maximize stress resilience while also defining a novel link between ER- phagy and proteostasis regulation.

physiology↗

bioRxiv2024

Loss of FIC-1-mediated AMPylation activates the UPRER and upregulates cytosolic HSP70 chaperones to suppress polyglutamine toxicity

Targeted regulation of cellular proteostasis machinery represents a promising strategy for the attenuation of pathological protein aggregation. Recent work suggests that the unfolded protein response in the endoplasmic reticulum (UPRER) directly regulates the aggregation and toxicity of expanded polyglutamine (polyQ) proteins. However, the mechanisms underlying this phenomenon remain poorly understood. In this study, we report that perturbing ER homeostasis in Caenorhabditis elegans through the depletion of either BiP ortholog, hsp-3 or hsp-4, causes developmental arrest in worms expressing aggregation-prone polyQ proteins. This phenotype is rescued by the genetic deletion of the conserved UPRER regulator, FIC-1. We demonstrate that the beneficial effects of fic-1 knock-out (KO) extend into adulthood, where the loss of FIC-1-mediated protein AMPylation in polyQ-expressing animals is sufficient to prevent declines in fitness and lifespan. We further show that loss of hsp-3 and hsp-4 leads to distinct, but complementary transcriptomic responses to ER stress involving all three UPRER stress sensors (IRE-1, PEK-1, and ATF-6). We identify the cytosolic HSP70 family chaperone F44E5.4, whose expression is increased in fic-1-deficient animals upon ER dysregulation, as a key effector suppressing polyQ toxicity. Over-expression of F44E5.4, but not other HSP70 family chaperones, is sufficient to rescue developmental arrest in polyQ-expressing embryos upon hsp-3 knock-down. Finally, we show that knock-down of ire-1, pek-1, or atf-6 blocks the upregulation of F44E5.4 in fic-1-deficient worms. Taken together, our findings support a model in which the loss of FIC-1-mediated AMPylation engages UPRER signaling to upregulate cytosolic chaperone activity in response to polyQ toxicity.

cell biology↗