title: Morphological remodeling ofC. elegansneurons 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 usedCaenorhabdits elegansto 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 transgenicC. elegansstrain 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.
authors.affiliation: Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK, USA.
authors.forename: Elena M
authors.initials: EM
authors.lastname: Vayndorf
authors.affiliation: Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK, USA; Department of Biology and Wildlife, University of Alaska Fairbanks, Fairbanks, AK, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Scerbak
authors.affiliation: Department of Biology and Wildlife, University of Alaska Fairbanks, Fairbanks, AK, USA.
authors.forename: Skyler
authors.initials: S
authors.lastname: Hunter
authors.affiliation: Warnell School of Forestry and Natural Resources, University of Georgia, Athens, GA, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Neuswanger
authors.affiliation: Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors.forename: Marton
authors.initials: M
authors.lastname: Toth
authors.affiliation: Department of Neuroscience, CRCHUM, University of Montreal, Montreal, QC, Canada.
authors.forename: J Alex
authors.initials: JA
authors.lastname: Parker
authors.affiliation: Laboratory of Neuronal Cell Biology and Pathology, Centre National de la Recherche Scientifique, Paris, France; Sorbonnes Universités, UPMC Univ Paris 06, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Neri
authors.affiliation: Department of Molecular Biology and Biochemistry, Nelson Biological Laboratories, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Driscoll
authors.affiliation: Institute of Arctic Biology, University of Alaska Fairbanks, Fairbanks, AK, USA; Department of Biology and Wildlife, University of Alaska Fairbanks, Fairbanks, AK, USA.
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Taylor