While autophagy is key to maintain cellular homeostasis, tissue-specific roles of individual autophagy genes are less understood. To study neuronal autophagy in vivo, we inhibited autophagy genes specifically in C. elegans neurons, and unexpectedly found that knockdown of early-acting autophagy genes, i.e., involved in formation of the autophagosome, except for atg-16.2, decreased PolyQ aggregates and increased lifespan, albeit independently of the degradation of autophagosomal cargo. Neuronal aggregates can be secreted from neurons via vesicles called exophers, and we found that neuronal inhibition of early-acting autophagy genes atg-7 and lgg-1/Atg8, but not atg-16.2 increased exopher formation. Moreover, atg-16.2 mutants were unable to form exophers, and atg-16.2 was required for the effects of early autophagy gene reduction on neuronal PolyQ aggregation, exopher formation, and lifespan. Notably, neuronal expression of full-length ATG-16.2 but not ATG-16.2 without a functional WD40 domain, important for non-canonical functions of ATG16L1 in mammalian cells, restored these phenotypes. Collectively, we discovered a specific role for C. elegans ATG-16.2 and its WD40 domain in exopher biogenesis, neuronal proteostasis, and lifespan determination, highlighting a possible role for non-canonical autophagy functions in both exopher formation and in aging.
Lysosomes are crucial for degradation and recycling of damaged proteins and cellular components. Therapeutic strategies enhancing lysosomal function are a promising approach for aging and age-related neurodegenerative diseases. Here, we show that an FDA approved drug sodium polystyrene sulfonate (SPS), used to reduce high blood potassium in humans, enhances lysosomal function both in C.elegans and in human neuronal cells. Enhanced lysosomal function following SPS treatment is accompanied by the suppression of proteotoxicity caused by expression of the neurotoxic peptides A and TAU. Additionaly, treatment with SPS imparts health benefits as it significantly increases lifespan in C.elegans. Overall our work supports the potential use of SPS as a prospective geroprotective intervention.
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