Implications of the prion-related Q/N domains in TDP-43 and FUS

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are clinically overlapping neurodegenerative disorders whose pathophysiology remains incompletely understood. ALS initiates in a discrete location, and typically progresses in a pattern consistent with spread of the degenerative process to involve neighboring regions of the motor system, although the basis of the apparent “spread” remains elusive. Recently mutations in two RNA binding proteins, TDP-43 and FUS, were identified in patients with familial ALS. In addition to being involved in numerous events related to RNA metabolism, each forms aggregates in neurons in ALS and FTLD. Recent evidence also indicates that both TDP-43 and FUS contain prion-related domains rich in glutamine (Q) and asparagine (N) residues, and in the case of TDP-43 this is the location of most disease causing mutations. This review discusses the potential relevance of the prion-related domains in TDP-43 and FUS in normal physiology, pathologic aggregation, and disease progression in ALS and FTLD.

Acknowledgements

R.H.B. is supported by the NIH/NINDS (K08 NS055980 and R01 NS069669), the Muscular Dystrophy Association (135428), the Children's Discovery Institute and holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund.

Figures and Tables

Figure 1 Line diagrams of TDP-43 and FUS showing the relationship between the prion-related domains and mutations in ALS and FTLD. The location of the prion-related domains are based on experimental findings of their interactions with polyglutamine inclusions13,14 and a prediction algorithm based on yeast prion domains.15 In the case of TDP-43, all but one of the ALS associated mutations are located in the prion-related Q/N rich domain. In FUS, the majority of ALS associated mutations occur in the C-terminal nuclear localization signal (NLS). However, a second cluster also occurs in or adjacent to the N-terminal prion related domain. NES, nuclear export signal; RRM, RNA binding domain; RGG, arginine, glycine, glycine repeat rich region; ZnF, zinc finger domain.