Axonal TDP-43 Dysregulation in ALS and Dementia

TDP-43蛋白病变是一系列神经退行性变中的标志性神经病理 疾病，包括ALS、FTD和阿尔茨海默氏症，仅举几例。常见演示文稿 TDP-43蛋白病变包括TDP-43从细胞核到细胞质的错误定位， 破坏其作为RNA结合蛋白(RBP)的已知功能。这种错误的本地化改变了全球 转录失调，如隐蔽外显子表达增加，以及影响 RNA的本地翻译。最近的研究表明，TDP-43被积极地输送到 轴突，由内溶酶体在运动蛋白马达上搭便车介导，它被干扰在 神经退行性疾病。此外，rna的运输和轴突翻译也很重要。 用于神经元功能和轴突维护。来自我们实验室和现有文献的初步数据， 提示KIF1a可能是促进TDP-43转运的一个候选激动素马达 进入轴突。在这里，我们假设TDP-43将RNA运输到轴突以促进局部 通过KIF1A蛋白进行翻译，KIF1A蛋白在ALS中受到干扰。由此产生的功能性TDP的损失- 轴突中的43阻止了从头合成蛋白质所需的关键转录本的定位 以及轴突的维护。这一致病事件的下游后果涉及 轴突蛋白转录组的紊乱，蛋白稳定期的丧失，以及 否则会支持轴突的完整性。

TDP-43 proteinopathy is a hallmark neuropathology among an array of neurodegenerative disorders, including ALS, FTD, and Alzheimer’s Disease to name a few. Common presentation of TDP-43 proteinopathy includes the mislocalization of TDP-43 from the nucleus to the cytoplasm, disrupting its known function as an RNA-binding protein (RBP). This mislocalization alters global transcriptional dysregulation, such as the increase of cryptic exon expression, as well as effecting local translation of RNAs. Recent studies suggests that TDP-43 is actively transported into the axon, mediated by endolysosomal hitch-hiking on kinesin motors, which is perturbed in neurodegenerative diseases. Moreover, the transport and axonal translation of RNA is important for neuronal function and axon maintenance. Preliminary data from our lab and existing literature, suggests that KIF1A might be a candidate kinesin-motor which facilitates the transport of TDP-43 into the axon. Here, we hypothesize that TDP-43 transports RNA to the axon to facilitate local translation through KIF1A protein, which is perturbed in ALS. The resultant loss of functional TDP- 43 in the axon prevents the localization of key transcripts necessary for de novo protein synthesis and maintenance of the axon. Downstream consequences of this pathogenic event involve the perturbance of the axonal proteotranscriptome, loss of proteostasis, and functional deficits that would otherwise support axon integrity.