Mechanisms of Protein Mislocalization in Neurodegenerative Disease



Journal Title

Journal ISSN

Volume Title



Fronto Temporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) are two fatal and rapidly progressing neurodegenerative diseases. A unifying characteristic of these diseases is the mislocalization of an RNA-binding protein, TDP-43. In unstressed cells, TDP-43 is predominantly nuclear and constantly shuttling to the cytosol; in ALS/FTLD, TDP-43 is aggregated in the cytosol. Two lines of evidence suggest this shift is a cause, rather than an effect, of disease. First, point mutations in the C-terminus of TDP-43, which enhance its aggregation, are a rare cause of familial ALS. Second, animal models which replicate the disease-linked redistribution of TDP-43 in motor neurons demonstrate the progressive muscle weakness and loss of spinal cord mass seen in patients. However, little is known about the cellular insults that promote TDP-43 mislocalization. My graduate work makes two contributions to this understanding. First, I elucidated a major determinant of normal TDP-43 trafficking. TDP-43 localization is governed by the balance between nuclear import and nuclear export. While a model for TDP-43 nuclear export had been proposed, there was no direct experimental evidence supporting it. I have shown that the proposed model of TDP-43 nuclear export is incorrect; the putative nuclear export signal (NES) does not mediate nuclear export, and TDP-43 nuclear export is XPO1 independent. Additionally, my data suggest no discrete trafficking signal within TDP-43. Rather, I propose that TDP-43 nuclear export is primarily driven by diffusion through the nuclear pore. Second, I focused on an upstream event known to affect TDP-43 localization: progranulin secretion. One genetic cause of FTLD is a single loss-of-function mutation in GRN, which causes progranulin haploinsufficiency. For reasons that are still unclear, a lifetime of progranulin haploinsufficiency in a patient causes FTLD with TDP-43 mislocalization. I focused on how a subset of GRN mutations- the signal sequence mutations- prevent progranulin secretion. I found that the W7R and A9D mutations disrupt co-translational recruitment of the targeting factor SRP (Signal Recognition Particle). This triggers a quality control pathway called RAPP (Regulation of Aberrant Protein Production), which results in degradation of both mutant protein and mutant mRNA. Thus, RAPP mediates progranulin haploinsufficiency in these patients.

General Notes

Table of Contents


Related URI