Axonal TDP-43 Dysregulation in ALS and Dementia

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

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.