Biology subjects

Voelkl, K.

Publications and source records attributed to Voelkl, K..

3 recordsLinked to original sources

bioRxiv2025

snRNA-seq of Huntington's disease mice reveals vulnerability profiles of cortical cell types

A common feature of neurodegeneration is selective vulnerability, where certain neurons succumb to disease, while others remain spared. The molecular underpinnings of these differences remain elusive. Here, we performed transcriptomic profiling of the motor cortex in a mouse model of Huntingtons disease (HD), an incurable hereditary movement disorder caused by a CAG repeat expansion in the Huntingtin gene. Strikingly, single-nucleus RNA-sequencing revealed a clear transcriptomic separation of HD and control samples within the vulnerable glutamatergic, but not disease-resistant GABAergic cell clusters. Tissue sampling at different time points allowed us to delineate a two-stage disease trajectory with distinct changes at early and late stages. Analysis of differentially expressed genes demonstrated progressive dysregulation of neuronal cell-type identity and upregulation of ER-phagy receptors. Mechanistic investigations in cellular HD models revealed increased ER-phagy, while knockdown of the ER-phagy receptor Tex264 resulted in elevated levels of the ER stress marker BiP, suggesting a protective role of ER-phagy in HD. Taken together, these findings advance our understanding of differential neuronal vulnerability, and identify ER-phagy as a new pathway in HD pathogenesis.

neuroscience↗

bioRxiv2023

Neuroprotective effects of hepatoma-derived growth factor in models of Huntington's disease

Huntingtons disease (HD) is a movement disorder caused by a mutation in the Huntingtin gene, that leads to severe neurodegeneration and inevitable death of the patients. Molecular mechanisms of HD are still not sufficiently understood, and no cure is currently available. Here, we demonstrate neuroprotective effects of hepatoma-derived growth factor (HDGF) in cellular and mouse models of HD. We show that HDGF expression levels in neuronal cell types inversely correlate with cellular vulnerability to HD. Moreover, lack of endogenous HDGF shortened lifespan and worsened rotarod performance of R6/2 HD model mice. AAV-mediated delivery of HDGF into the brain reduced mutant Huntingtin inclusion body load, but had no significant effect on motor behavior or lifespan. Interestingly, both nuclear and cytoplasmic versions of HDGF were equally efficient in rescuing mutant Huntingtin toxicity in cell culture models of HD. Moreover, extracellular application of a recombinant HDGF protein improved viability of mutant Huntingtin-expressing primary neurons and reduced mutant Huntingtin aggregation in neural progenitor cells differentiated from human patient-derived induced pluripotent stem cells (iPSCs). Our findings provide new insights into the pathomechanisms of HD and suggest neuroprotective potential of HDGF in neurodegeneration.

neuroscience↗

bioRxiv2020

Novel proteostasis reporter mouse reveals different effects of cytoplasmic and nuclear aggregates on protein quality control in neurons

The cellular protein quality control machinery is important for preventing protein misfolding and aggregation, and decline in protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how proteostasis capacity of neurons changes in different diseases is not yet sufficiently understood, and progress in this area has been hampered by the lack of tools to monitor proteostasis in mammalian models. Here, we have developed reporter mice for in vivo analysis of neuronal proteostasis. The mice express EGFP-fused firefly luciferase (Fluc), a conformationally unstable protein that requires chaperones for proper folding and sensitively reacts to proteotoxic stress by formation of intracellular Fluc-EGFP foci and by reduced luciferase activity. Using these mice, we provide evidence for proteostasis decline in the aging brain. Moreover, we find a marked impairment in proteostasis in tauopathy mice, but not in Huntingtons disease mice. Mechanistic investigations in primary neuronal cultures demonstrate that cytoplasmic, but not nuclear, aggregates cause defects of cellular protein quality control. Thus, the Fluc-EGFP reporter mice enable new insights into proteostasis alterations in different diseases.

neuroscience↗