Elucidating the synergistic role of tau and α-synuclein in neurodegeneration and cognitive decline through mitochondrial dysfunction

Augusta University, Augusta GA

Investigators

Abstract

Project Summary Alzheimer’s disease (AD), followed by Parkinson’s disease (PD), are the most common age-associated neurodegenerative diseases, neither with cure or sufficient disease-modifying treatment. AD is primarily defined by pathologies of amyloid- and tau proteins, while PD is defined by -synuclein (α-syn) protein deposits. However, these pathologies often coexist in both AD and PD and may act synergistically to enhance neurodegeneration. In line with this, co-morbid tau and α-syn pathologies have been found in post-mortem brain tissue of AD and PD patients. One region affected in both diseases is the basal forebrain, a region associated with cognition, in which the loss of learning and memory associated neurons in both AD and PD is thought to underlie cognitive decline and dementia. Impaired mitochondrial function has also been associated with AD and PD, with recent studies demonstrating tau and α-syn disrupting mitochondrial respiration in AD and PD cell cultures and rodent models. However, it is currently not known how tau and α-syn aggregation synergistically affect neuronal mitochondria and how this may contribute to cognitive dysfunction and neuron death. To model this co-pathology, I am using C. elegans due to its rapid aging, conserved neurobiology, and ease of genetic manipulation, allowing for highly mechanistic investigations linking molecular mechanisms with behavior. Transgenic strains expressing human tau, human α-syn, or human tau and human α-syn together in all neurons will be used to model proteotoxicity in AD and PD contexts. My preliminary data indicates that the combination of tau and α-syn enhances cognitive decline compared to tau alone or α-syn alone. Neurodegeneration will be investigated through imaging studies, evaluating neurons within the learning and memory circuitry when tau and α-syn are present. Biochemical analyses will reveal the pathological species of tau and α-syn associated with the co-pathology. The potential reversibility of neurodegeneration and cognitive decline will be tested through the degradation of tau, α-syn, or their combination via the auxin-inducible degradation system in live C. elegans. To study mitochondrial dysfunction, mitochondrial morphology and bioenergetics will be assessed when tau and α-syn are expressed in all neurons. Morphological data will be obtained via super-resolution microscopy, while respiration will be measured using Seahorse. Novel mitochondrial genes altered by the combination of tau and α-syn will be identified by RNA-sequencing specifically in learning and memory neurons. The top genes will be tested for their role in neurodegeneration and cognitive decline. Finally, we will verify the role of mitochondrial respiration in the toxicity of tau and α-syn co-pathology using human neuronal iPS cells. The overall goal of this work is to shed light on the mechanisms of mitochondrial dysfunction and neurodegeneration in AD and PD and identify potential therapeutic targets to treat cognitive decline.