Lysosomal dysregulation contributes to HAND

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SUMMARY The lysosomal function is essential for protecting neuronal homeostasis. A precise lysosome activity and dynamics are crucial to maintaining the degradation of lipids, misfolded proteins, and damaged organelles. Undigested products from the lysosome are neurotoxic and responsible for neurodegenerative diseases. Lysosomal dysfunction can lead to the aggregation of alpha-synuclein (-Syn), associated with cognitive, speech, and movement disorders often observed in patients suffering from Parkinson's disease. Clinical studies also showed that a significant number of HIV-1 infected patients suffer from neurological disorders, including cognitive, speech, and motor disorders that affect their gait and body agility, like parkinsonian-like symptoms or Parkinsonism. However, the mechanisms involved remain unclear. Our goal is to characterize how HIV-1 decreases neuronal clearance leading to a progression of HIV-associated neurocognitive disorders like motor dysfunction. We showed that HIV-1 Vpr protein: (i) triggers the accumulation of -Syn in neurons after decreasing the lysosomal acidification; (ii) disrupts the organelles trafficking by provoking the loss of microtubules activity; and (iii) deregulates the lysosome movement and positioning. Proteomic analysis showed deregulation in the expression levels of several proteins involved in lysosomal maturation in Vpr-treated neurons. Among these is the SNAPIN protein that regulates lysosomal acidification, positioning, and trafficking in neurons. Therefore, using neuronal cells, iPSCs, and an animal model, we propose to determine the post-translational regulation of SNAPIN in its environment and by HIV-1 Vpr (Aim 1). Since the transport of lysosomes into the axon is necessary for efficient degradation, we will explore the impact of Vpr-induced SNAPIN dysregulation on lysosomal transport (Aim 2). Finally, lysosomal degradation is an essential part of protein homeostasis; we will use a multi-omics approach to identify pre-clinical markers (that aim to restore SNAPIN and lysosomal functions) in the presence and absence of Vpr and SNAPIN and assess the metabolic disturbances underlying neurological impairment resulting in long-term neurological outcomes (Aim 3). This study will bring a better understanding of the general regulation of the autophagic clearance by HIV-1 Vpr and SNAPIN and highlight how lysosomes are reshaped during HIV-1 infection and affect different longevity-promoting pathways.