The Role of Abnormal Inter-Organelle Communication in the Pathogenesis of Tauopathy

Rutgers, The State Univ Of N.J., New Brunswick NJ

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Abstract

PROJECT SUMMARY Hyperphosphorylation and aggregation of microtubule-associated tau is a pathological hallmark of tauopathies, which constitutes one of the two defining features of Alzheimer’s disease (AD). In AD, tau pathology correlates with neuronal death and cognitive dysfunction better than amyloid plaques. Thus, understanding the pathogenic mechanisms underlying tau buildup and toxicity is of great importance in developing tau-targeting therapy for treating AD and other tauopathy diseases. Pathologically phosphorylated tau (p-tau) is known to be degraded within lysosomes after sequestration within autophagosomes/autophagic vacuoles (AVs). Earlier studies of tauopathy patient brains demonstrated autophagy abnormalities—aberrant accumulation of AVs, suggesting autophagy failure in the removal of p-tau as a fundamental component of pathological progression. The underlying mechanism, however, remains elusive. Recent breakthroughs in the field make it increasingly evident that organelles engage in extensive communication through membrane contacts, and that deregulation of inter-organelle communication is an emerging mechanism underlying aging and neurodegeneration. Our preliminary findings revealed, for the first time, that AVs were accumulated at the synaptic terminals of tauopathy brains. Most interestingly, these AVs were loaded with p-tau, in close contact with mitochondria, and became immotile, which likely prevents AV retrograde transport and cargo clearance in tauopathy neurons. This AV-mitochondria (Mito) contact hyper-tethering was associated with reduced expression of the contact release factor TBC1D15, a Rab7 GTPase-activating protein (GAP), that stimulates Rab7 GTP hydrolysis for Rab7 inactivation. Importantly, neuronal TBC1D15 deficiency recapitulated excessive AV-Mito tethering coupled with mitochondrial deficits. Overexpression of TBC1D15 in cultured tauopathy neurons reversed such AV-Mito contact release defects, leading to reduced AV accumulation and improved mitochondrial function. Based on these studies, we hypothesized that TBC1D15 deficiency causes AV-Mito contact hyper-tethering, which hampers AV retrograde transport-mediated removal of p-tau-loaded AVs from synaptic terminals and triggers mitochondrial defects, thereby contributing to the pathogenesis of tauopathy. Therefore, TBC1D15 overexpression reverses autophagy and mitochondrial deficits and attenuates tauopathy- related pathologies. Tau mouse models with TBC1D15 overexpression will be carefully characterized. We will determine the mechanisms underlying TBC1D15 reduction in tauopathy and explore how AV-Mito contact release deficiency contributes to autophagy failure and mitochondrial defects in tauopathy. The successful completion of this study will advance the understanding of a critical early step in tauopathy pathogenesis and may provide new molecular and pharmacological targets for drug development in tauopathy diseases including AD and also have implications for studying other neurodegenerative disorders and aging in general.