Morphological remodeling of C. elegans neurons during aging is modified by compromised protein homeostasis

Abstract

Understanding cellular outcomes, such as neuronal remodeling, that are common to both healthy and diseased aging brains is essential to the development of successful brain aging strategies. Here, we used Caenorhabdits elegans to investigate how the expression of proteotoxic triggers, such as polyglutamine (polyQ)-expanded huntingtin and silencing of proteostasis regulators, such as the ubiquitin–proteasome system (UPS) and protein clearance components, may impact the morphological remodeling of individual neurons as animals age. We examined the effects of disrupted proteostasis on the integrity of neuronal cytoarchitecture by imaging a transgenic C. elegans strain in which touch receptor neurons express the first 57 amino acids of the human huntingtin (Htt) gene with expanded polyQs (128Q) and by using neuron-targeted RNA interference in adult wild-type neurons to knockdown genes encoding proteins involved in proteostasis. We found that proteostatic challenges conferred by polyQ-expanded Htt and knockdown of specific genes involved in protein homeostasis can lead to morphological changes that are restricted to specific domains of specific neurons. The age-associated branching of PLM neurons is suppressed by N-ter polyQ-expanded Htt expression, whereas ALM neurons with polyQ-expanded Htt accumulate extended outgrowths and other soma abnormalities. Furthermore, knockdown of genes important for ubiquitin-mediated degradation, lysosomal function, and autophagy modulated these age-related morphological changes in otherwise normal neurons. Our results show that the expression of misfolded proteins in neurodegenerative disease such as Huntington’s disease modifies the morphological remodeling that is normally associated with neuronal aging. Our results also show that morphological remodeling of healthy neurons during aging can be regulated by the UPS and other proteostasis pathways. Collectively, our data highlight a model in which morphological remodeling during neuronal aging is strongly affected by disrupted proteostasis and expression of disease-associated, misfolded proteins such as human polyQ-Htt species. Misfolded proteins and disrupted protein maintenance can lead to aging-related changes in neuron shape. Elena Vayndorf from the University of Alaska Fairbanks and colleagues in the US, Canada and France studied a strain of nematode Caenorhabditis elegans in which selected neurons express part of the human gene responsible for Huntington’s disease, which is an aging-related, neurodegenerative disorder. The researchers also blocked expression of genes involved in protein manufacture, folding, trafficking and degradation in healthy neurons. With both experimental manipulations, they observed changes in the morphology of the animal’s neurons that normally occur during aging. Given the similarities between C. elegans and human neurons, the authors propose that drugs targeting the cellular pathways that guide protein maintenance could help retain brain function in age-associated neurological diseases like Huntington’s.