Age-dependent dynamics of neuronal VAPBALSinclusions in the adult brain

Abstract

ABSTRACTAmyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive and fatal disease, caused by the degeneration of upper and lower motor neurons within the brain and spinal cord in the ageing human. The dying neurons contain cytoplasmic inclusions linked to the onset and progression of the disease. Here, we use aDrosophilamodel ofALS8 (VAPP58S)to understand the modulation of these inclusions in the ageing adult brain.The adultVAPP58Sfly shows progressive deterioration in motor function till its demise 25 days post-eclosion. The density of VAPP58S-positive brain inclusions is stable for 5-15 days of age. In contrast, adding a single copy ofVAPWTto theVAPP58Sanimal leads to a large decrease in inclusion density with concomitant rescue of motor function and lifespan. ER stress, a contributing factor in disease, shows reduction with ageing for the disease model. Autophagy, rather than the Ubiquitin Proteasome system, is the dominant mechanism for aggregate clearance.We explored the ability ofDrosophilaValosin-containing protein (VCP/TER94), theALS14locus, which is involved in cellular protein clearance, to regulate age-dependent aggregation. Contrary to expectation,TER94overexpression increased VAPP58Spunctae density, while its knockdown led to enhanced clearance. Expression of a dominant positive allele,TER94R152H,further stabilised VAPP58Spuncta, cementing roles for anALS8-ALS14axis. Our results are explained by a mechanism where autophagy is modulated byTER94knockdown.Our study sheds light on the complex regulatory events involved in the neuronal maintenance of ALS8 aggregates, suggesting a context-dependent switch between proteasomal and autophagy-based mechanisms as the larvae develop into an adult. A deeper understanding of the nucleation and clearance of the inclusions, which affect cellular stress and function, is essential for understanding the initiation and progression of ALS.