On the role of v-ATPase V0a1–dependent degradation in Alzheimer Disease

Abstract

Defective autophagy and lysosomal degradation are hallmarks of numerous neurodegenerative disorders. Vesicular ATPases are intracellular proton pumps that acidify autophagosomes and lysosomes. V0a1 is a key component of the v-ATPase that is only required in neurons in Drosophila melanogaster. We have recently shown that loss of V0a1 in Drosophila photoreceptor neurons leads to slow, adult-onset degeneration.1 Concurrently, Lee et al.2 reported that V0a1 fails to localize to lysosomal compartments in cells from Presenilin 1 knock-out cells. Together these two reports suggest that a neuronal V0a1-dependent degradation mechanism may be causally linked to Alzheimer pathology. Indeed, we now show that loss of V0a1 makes Drosophila neurons more susceptible to insult with human Alzheimer-related neurotoxic Aβ and tau proteins. Furthermore, we discuss the potential significance of the discovery of the neuron-specific degradation mechanism in Drosophila for intracellular degradation defects in Alzheimer Disease.