Elucidating The Aberrant TDP-43 Species That Promote Neurodegeneration

TDP-43功能障碍是一系列神经退行性疾病的基础，统称为TDP-43

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.