Adaptor protein WDFY3 is neuroprotective by counteracting age-dependent decline in proteostasis

Abstract

Age-dependent decline in proteostasis increases vulnerability of neuronal cells to oxidative stress, altered energy homeostasis and protein aggregation. Recent studies have suggested an adaptor role for BEACH-domain containing proteins (BDCPs) in autophagy-mediated clearance of protein aggregates in neurodegenerative models. Alterations in BDCPs result in protein aggregation and shortened lifespan in Drosophila. However, the exact mechanism by which they regulate autophagy and alleviate neurodegenerative toxicity remains unclear. Here, we report the characterisation of WDFY-3, a BDCP in Caenorhabditis elegans. Like its Drosophila homologue blue cheese, WDFY-3 is widely expressed in the nerve ring and along the entire length of axonal projections, supporting the possibility of having neuron-specific functions. Our results show that wdfy-3 is not required to induce autophagy genetically and at the protein levels in aged HD animals. Additionally, loss of wdfy-3 shortens the lifespan and reduces motility of C. elegans. Surprisingly during aging, there was a reduction in neuronal aggregates in the absence of wdfy-3, suggesting the protective role of WDFY-3 as a stabiliser that sequesters polyglutamine aggregates into inclusion bodies, further reducing toxicity. Together, our data point to the potential role of WDFY-3 in sequestering toxic aggregates upon age-dependent decline in proteostasis.