Impact of neuronal lysosomal dysfunction on RNA transport and local translation in Alzheimer’s disease

Alterations of the endolysosomal system are an early feature of Alzheimer’s disease (AD), preceding amyloid deposition, neuronal loss and cognitive impairment. Endolysosomes appear directly implicated in neuronal homeostasis and survival through their participation in local translation. Herein, mRNAs, bound to RNA-binding proteins (RBPs) in ribonucleoprotein complexes, appear to hitchhike on endolysosomes during axonal transport to reach distally located synapses. Moreover, recent studies demonstrated that endolysosomes may serve as sites for local protein synthesis in neurons. Interestingly, many neurodegenerative diseases are marked by endolysosomal defects, which may directly impact this process. While protein synthesis deficits were recently reported in ALS/FTD, this remains largely unexplored in the context of AD. In the context of AD, several studies have shown that altered expression of presenilins (knock-out or familial AD-linked mutations), the catalytic components of γ-secretase, causes endolysosomal abnormalities. We therefore argue that this may impact on axonal transport of RNPs on endolysosomes and local translation in neurons, with direct repercussions on organellar and synaptic functioning. In this project, we will use super-resolution and live imaging to assess the dynamic association of RNAs/RBPs with endolysosomes and whether this is affected by KO or familial AD mutations, using iPSC derived human neurons. We will optimize assays for proximity ligation approaches to identify associated RNAs/RBPs, and which would allow to identify affected pathways and organelles that depend on local translation. These approaches will allow us to unravel whether the endolysosomal defects observed in AD are associated with impairments in RNA transport and local translation, together disrupting axonal homeostasis and contributing to neurodegeneration.