From human genetics to functional characterization in fruit flies and back: role of novel Alzheimer's disease risk factor SNX32 in maintenance of synaptic transmission and proteostasis

• Applicant: Dr. Shabab Hannan, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 502255921

Large scale genome-wide association studies (GWAS) and sequencing analysis have accelerated the discovery of novel genes implicated in the pathogenesis of Alzheimer's disease (AD). While discoveries from human genetic studies continue to rise, functional validation from model systems providing mechanistic insights on novel genes have been lagging behind. Consequently, translation of human genetic studies to new therapies has been hindered. Furthermore, one pitfall in GWAS is that the assignment of genes to risk loci is ambiguous. A novel approach circumvented this uncertainty by incorporating protein and transcript signatures with GWAS and implicated SNX32 as novel AD-associated gene. SNX32 is classified in the sorting nexin family of proteins with largely unknown functions and hence functional data linking dysregulation to AD pathophysiology is missing. Sorting nexins regulate proteostasis and mediate protein sorting in the retromer complex involved in endosomal trafficking between trans-golgi network and plasma membrane. Loss of retromer complex function cause impairments in synaptic transmission and proteostasis. Recent studies in Prof. Joshua Shulman's lab has taken advantage of the impressive genetic conservation in Drosophila, rapid turnover time and plethora of genetic tools in the fruit fly model to provide functional insights on AD risk factor genes and pathways. I hypothesize that loss of SNX32 will impair synaptic transmission and autophagy, enlargement of endolysosomal compartments and progressive age-dependent neurodegeneration. Exploiting excellent genetic tools in fruit fly, I will investigate the role of SNX32 in vivo in neuronal function and proteostasis, examining the evolutionary conserved ortholog Snx6 (dSNX32). Using loss of function models, I will examine the impact of loss of dSNX32 in neuronal function by studying (1) adult locomotor behavior and survival, (2) neuronal development and (3) synaptic transmission. Next, to shed light on the role of dSNX32 in proteostasis in vivo, I will (4) analyze subcellular localization of dSNX32 in endosomal compartments, (5) establish role of dSNX32 in maintenance of proteostasis and (6) examine status of endolysosomal compartments following loss of function. These experiments are aimed to define the functions of SNX32 in vivo to mechanistically link dysregulation to AD pathogenesis. A Walter Benjamin Fellowship would be a great boost, providing me impetus to learn the most cutting edge techniques in Drosophila. It will give me the great opportunity to extend my expertise and participate in translational AD consortium research with exposure to large-scale patient data and mammalian modeling while developing new ideas and preparing to become an independent group leader.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Joshua Shulman, Ph.D.