The cytoskeletal protein Plectin regulates Tau‐induced neurotoxicity in Alzheimer’s Disease

Abstract

AbstractBackgroundThe genetic causes for most cases of Alzheimer’s disease (AD) and the underlying biology of pathogenesis remain unknown. Recent large scale proteomics studies on AD patient brains have identified novel protein networks and targets that are highly correlated with AD diagnosis and neuropathology. The most significantly AD‐correlated protein network identified contains the cytoskeletal protein Plectin (PLEC) as a network hub. PLEC functions to crosslink different cytoskeletal components and plays a role in axonal transport of synaptic proteins. Considering that microtubule associated protein‐Tau (MAPT) dysfunction is an AD hallmark, we hypothesize that PLEC dysfunction increases AD susceptibility by disrupting cytoskeletal homeostasis and synaptic function.MethodUtilizing a combination of genetic and proteomic analyses, we validate Plectin as a potential AD risk factor. We assessed the role of PLEC in Tau‐induced neurotoxicity in the animal model Drosophila melanogaster and human neuronal cell culture. Furthermore, we have also elucidated PLEC mutant neurodegenerative phenotypes independent of Tau overexpression in the fly. Immunoprecipitation‐mass spectrometry (IP‐MS) analysis was performed to define a Drosophila Plectin protein‐protein interaction network in adult brains. This network will serve as the basis for cross‐species analysis of protein networks.ResultThe Drosophila homolog of Plectin (dPLEC) is ubiquitously expressed within the adult brain with strong enrichment in neuronal rich tissues. Using Drosophila models of human tauopathy, dPLEC regulates age dependent Tau‐induced neurotoxicity and locomotor dysfunction. Plus, altering levels dPLEC regulates Tau‐phosphorylation in both adult Drosophila brains and human neurons. In the absence of Tau overexpression, dPLEC functions in light‐induced neuronal transmission confirming its role in normal neuronal function. Continued mechanistic analysis in both Drosophila and human neuronal cultures will determine PLEC’s role in AD neuropathogenesis and elucidate the underlying role of the cytoskeleton in AD susceptibility. To that end, we generated an endogenous GFP‐tagged dPLEC (dPLEC‐GFP) and performed immunoprecipitation‐mass spectrometry (IP‐MS) analysis to identify dPLEC protein interactors. Several cytoskeletal and synaptic proteins were identified and are currently being tested for their role in Tau‐induced neurodegeneration and synaptic dysfunction.ConclusionWe functionally validate the AD target PLEC as a regulator of Tau‐induced neurodegeneration and identify PLEC as a regulator of Tau dynamics and neuronal function.