Shared Mechanisms of Tau Toxicity Among Neurodegenerative Diseases

Stanford University, Stanford CA

Investigators

Abstract

Project Summary Many neurodegenerative diseases share neuropathological and clinical features. If this overlap is any indication of shared pathogenic mechanism, therapeutic targeting of such mechanism may have the potential to alleviate a broad spectrum of diseases. Hyperphosphorylation and aggregation of tau is a pathological hallmark of primary tauopathies such as Frontotemporal Dementia (FTD) and Progressive Supranuclear Palsy (PSP) and secondary tauopathies that include some of the most common neurodegenerative diseases such as Alzheimer's disease (AD), and possibly Parkinson's disease (PD) and Huntington's disease (HD). Tau abnormality and beneficial effects of tau reduction have also been observed in experimental models of autism, depression, epilepsy, stroke, and traumatic brain injury, even though these models may not develop prominent intraneuronal accumulations of tau aggregates as in primary or secondary tauopathies. Dysfunctional mitochondria is also a prominent feature of the above diseases. Whether tau abnormality and mitochondrial dysfunction are mechanistically connected and can be targeted together to treat common neurodegenerative diseases is a key question this project aims to address. To effectively target tau, a deeper understanding of its normal physiological function as well as its pathogenic role in disease is needed. Previous studies revealed extensive tau interaction with mitochondrial proteins, and studies in animal models and humans have revealed a specific link between tau and mitochondrial complex-I (C-I) dysfunction, although the exact mechanism is unclear. C-I is the largest multisubunit complex of the respiratory chain, containing 45 subunits in humans. Despite the essential role of C-I in mitochondrial function and bioenergetics, partial but not complete inhibition of its specific subunits offered beneficial effects on lifespan or age-related neurodegenerative disease across species. The molecular mechanism underlying this phenomenon is not well understood. Our recent studies on C-I mediated reverse electron transfer (RET) have offered some clues. Under certain thermodynamic conditions, for example when forward electron transport (FET) is blocked while membrane potential (MMP) is still high, RET will prevail, moving electrons from CoQH2 back to the NAD+/NADH binding site of C-I, producing a significant amount of ROS (RET-ROS) and lowering NAD+/NADH ratio. RET is considered a major source of mitochondrial ROS production, and our recent studies indicate that it is also a main determinant of mitochondrial and cellular NAD+/NADH ratio. In Preliminary Studies, we find that RET is activated during aging and in age-related neurodegenerative diseases such as FTD, AD, PD, and HD, and that genetic reduction of select C-I proteins involved in RET or pharmacological inhibition of RET is beneficial in these conditions. The goal of this study is to use in vivo animal models and human iPSC-derived cell culture models to investigate the mechanism of RET regulation by tau and how tau-induced RET deregulation contributes to a broad spectrum of age-related neurodegenerative diseases including AD and AD related dementias (AD/ADRD).