TDP-43 dysfunction underlies a spectrum of neurodegenerative diseases collectively known as TDP-43 proteinopathies, which are characterized by neuronal loss, behavioral abnormalities, and ultimately death. Surprisingly, little is known about how TDP-43 undergoes such a dramatic transformation that initiates disease progression. Recently, we discovered that TDP-43 is subject to reversible lysine acetylation, a modification within TDP-43?s RNA-binding domain that has a remarkable effect; it disengages TDP-43 from its target mRNAs and accelerates TDP-43?s propensity to aggregate. Indeed, acetylated TDP-43 inclusions were detected in motor neurons of amyotrophic lateral sclerosis (ALS) patients, suggesting a role for this aberrantly modified form of TDP-43 in disease pathogenesis. We leveraged this intriguing finding to generate the first CRISPR-based, non-transgenic TDP-43 mouse model containing an acetylation-mimicking mutation, thus producing a physiologically relevant model of TDP-43 proteinopathy. We hypothesize that TDP-43 acetylation drives neurodegeneration and disease progression, which can now be directly tested in vivo. Our preliminary data already show evidence of TDP-43 pathology, nuclear TDP-43 clearing, and prominent behavioral defects in mutant mice.
In Aim -1, we will use histology, biochemical, and behavior approaches to fully characterize the neurodegenerative phenotype.
In Aim -2, we shed light on the therapeutic potential of activating the master transcription factor HSF1, or specific downstream chaperones, to induce a highly coordinated transcriptional cascade capable of suppressing acetylated TDP-43 dysfunction and restoring nuclear TDP-43 levels. Finally, in Aim-3, we will uncover early-stage perturbations in the transcriptome that occur in response to acetylated TDP-43, but emerge prior to overt neurodegeneration and behavioral defects. Our proposal is significant since it will highlight an aberrant form of TDP-43 as a plausible therapeutic target, it will pinpoint specific chaperone responses as new avenues to detoxify neurons, and it will illuminate transcriptional dysregulation as a critical pathomechanism associated with neurodegeneration. Our proposal is also innovative since we will shed light on aberrant TDP-43 modifications as plausible triggers for disease onset or progression.

Public Health Relevance

TDP-43 dysfunction is now firmly linked to the neurodegeneration observed in a spectrum of human diseases including both motor and cognitive disorders alike. Our study will establish a new causative role for aberrantly modified TDP-43 in driving disease pathogenesis, highlighting acetylated TDP-43 as a potential target for future therapies. By modulating the acetylation machinery to fine-tune TDP-43 function, we could potentially detoxify diseased neurons, prevent neurodegeneration, and alleviate behavior symptoms in a range of diverse neurological conditions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Gubitz, Amelie
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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