The Role of Mitochondria in TDP-43 Proteinopathy

Project: Research project

Project Details


Our goal is to understand molecular pathogenesis of neurodegenerative disorders associated with RNA binding protein TDP-43, known as TDP-43 proteinopathy. This is a spectrum of diseases characterized by the presence of TDP-43 positive protein inclusion bodies in the affected tissues. TDP-43 proteinopathy is heterogeneous, including dementia and motor neuron diseases, such as frontotemporal lobar degeneration and amyotrophic lateral sclerosis (FTLD-TDP and ALS-TDP). A significant fraction of Alzheimer’s disease (AD) patients also show TDP-43 positive pathology. Although it has been published that TDP-43 is partially localized in mitochondria and causes mitochondrial dysfunction, conflicting data have been reported. The role of mitochondria in the pathogenesis of TDP-43 proteinopathy remains unclear. We have obtained exciting preliminary data that mitochondrial damage is a pathologic feature in FTLD-TDP brains and that expression of TDP-43 induces mitochondrial dysfunction and mitochondrial stress response (MSR). Together with published work, our preliminary data led us to propose a working hypothesis in which TDP-43-induced mitochondrial dysfunction and MSR contribute to the pathogenesis of TDP-43 proteinopathy. During the early stage, balanced MSR up-regulates mitoprotease(s) which degrade TDP-43 and protect against TDP-43 cytotoxicity. With disease progression, excessive mitochondrial TDP-43 accumulation may dysregulate MSR and disrupt mitochondrial proteostasis, resulting in irreparable mitochondrial damage and neurodegeneration. We propose to systematically characterize molecular signatures of MSR induced by TDP-43 and rigorously test our working hypothesis. We will take an integrated approach using molecular, biochemical and cell biological assays together with animal models, patient samples and patient iPSC-derived neurons to examine the role of TDP-43 in MSR, to characterize mitoproteases critical for TDP-43 degradation and neurotoxicity and to determine the role of dysregulated MSR in the disease pathogenesis. By genetic and pharmacologic manipulations, we will determine if enhancing mitoproteostasis may ameliorate TDP-43 induced neurodegeneration. Successful completion of the proposed study will not only provide new insights into the role of mitochondrial damage and mitochondrial stress response in neurodegenerative diseases associated with TDP-43, but also establish the feasibility for future therapeutic intervention.
Effective start/end date9/30/186/30/23


  • National Institute of Neurological Disorders and Stroke (5R01NS107396-05)


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