Regulation of ATAD3A in TDP43-associated ALS/FTD - PROJECT SUMMARY The nuclear exclusion and subsequent cytoplasmic accumulation of TAR DNA-binding protein, 43 kDa (TDP43), are hallmark features in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic accumulation of TDP43 is observed in over 50% of FTD cases and almost 95% of ALS cases. This accumulation is associated with various cellular abnormalities, including mitochondrial defects, inflammation, and neurodegeneration. While current efforts in ALS and FTD research largely target the downstream effects of cytoplasmic TDP43, understanding the mechanisms causing TDP43 cytoplasmic localization is vital for preventing disease pathogenesis and developing effective treatments for ALS, FTD, and other TDP43-related conditions. Our preliminary studies revealed a previously unidentified role for the protein ATAD3A in TDP43-mediated neuropathology. ATAD3A, an AAA-ATPase protein located at mitochondrial contact sites, regulates mitochondrial dynamics, mitochondrial genome stability, and cholesterol metabolism and trafficking. Aberrant ATAD3A levels, or mutations in the ATAD3A gene, are associated with neurodegeneration, highlighting the critical role of functional ATAD3A in mitochondrial homeostasis and neuronal survival. Expression of ATAD3A mRNA is reduced in ALS and FTD, and ATAD3A transcript is a direct target of TDP43, suggesting a link between ATAD3A deficiency and ALS/FTD pathogenesis. Intriguingly, we found that decreasing the expression of either gene (ATAD3A or TDP43) influences the expression behavior of the other. Furthermore, our preliminary studies support the scientific premise that TDP43, in healthy cells, stabilizes ATAD3A. However, in pathological conditions, it suppresses ATAD3A mRNA expression, leading to a gain-of-function aberration. This negative regulatory action on ATAD3A causes the cytoplasmic toxicity of TDP43 and the associated neuropathological manifestations seen in ALS/FTD. We will perform three aims to test our hypothesis. Aim 1 is to determine the causes and consequences of ATAD3A loss in TDP43-associated ALS/FTD models. Aim 2 is to assess whether ATAD3A replacement reduces motor neuron toxicity in ALS/FTD models. Aim 3 is to uncover the mechanism by which ATAD3A loss contributes to TDP43 proteinopathy. Success in these studies will position ATAD3A as a pivotal molecule in TDP43 pathology, linking mitochondrial defects, neuroinflammation, and neurodegeneration. This research could significantly influence ALS/FTD research by spotlighting ATAD3A as a novel therapeutic target to mitigate TDP43 toxicity in ALS/FTD.
