Elucidating The Aberrant TDP-43 Species That Promote Neurodegeneration

TDP-43功能障碍是统称为TDP-43的一系列神经退行性疾病的基础 蛋白质病，其特征在于神经元损失、行为异常和最终死亡。 令人惊讶的是，人们对TDP-43如何经历如此戏剧性的转变并引发疾病知之甚少 进展最近，我们发现TDP-43是可逆的赖氨酸乙酰化，修饰 在TDP-43的RNA结合结构域中，具有显著的效果;它使TDP-43与其靶标分离 并加速TDP-43的聚集倾向。事实上，乙酰化的TDP-43内含物是 在肌萎缩侧索硬化症（ALS）患者的运动神经元中检测到，这表明这种异常的作用， TDP-43的修饰形式在疾病发病机制中的作用。我们利用这一有趣的发现， 基于CRISPR的非转基因TDP-43小鼠模型含有乙酰化模拟突变，因此 产生TDP-43蛋白质病的生理学相关模型。我们假设TDP-43 乙酰化驱动神经变性和疾病进展，现在可以直接在 vivo.我们的初步数据已经显示了TDP-43病理学的证据，细胞核TDP-43清除， 突变小鼠的显著行为缺陷。在Aim-1中，我们将使用组织学、生物化学和行为学 方法来充分表征神经退行性表型。在Aim-2中，我们阐明了治疗方法 激活主转录因子HSF 1或特异性下游分子伴侣的潜力，以诱导 能够抑制乙酰化TDP-43功能障碍的高度协调的转录级联， 恢复了TDP-43的核水平最后，在Aim-3中，我们将揭示宇宙中的早期扰动。 应答乙酰化TDP-43而出现的转录组，但在明显的神经变性和 行为缺陷我们的建议是重要的，因为它将突出一种异常形式的TDP-43作为一种合理的 治疗目标，它将查明特定的伴侣反应作为新的途径，以解毒神经元，它将 阐明转录失调是与神经变性相关关键病理机制。我们 该提案也是创新的，因为我们将阐明异常的TDP-43修改作为合理的触发因素， 疾病发作或进展。

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.