TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets

Emma L. Scotter, Han-Jou Chen, Christopher E. Shaw*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

212 Citations (Scopus)
206 Downloads (Pure)

Abstract

Therapeutic options for patients with amyotrophic lateral sclerosis (ALS) are currently limited. However, recent studies show that almost all cases of ALS, as well as tau-negative frontotemporal dementia (FTD), share a common neuropathology characterized by the deposition of TAR-DNA binding protein (TDP)-43-positive protein inclusions, offering an attractive target for the design and testing of novel therapeutics. Here we demonstrate how diverse environmental stressors linked to stress granule formation, as well as mutations in genes encoding RNA processing proteins and protein degradation adaptors, initiate ALS pathogenesis via TDP-43. We review the progressive development of TDP-43 proteinopathy from cytoplasmic mislocalization and misfolding through to macroaggregation and the addition of phosphate and ubiquitin moieties. Drawing from cellular and animal studies, we explore the feasibility of therapeutics that act at each point in pathogenesis, from mitigating genetic risk using antisense oligonucleotides to modulating TDP-43 proteinopathy itself using small molecule activators of autophagy, the ubiquitin-proteasome system, or the chaperone network. We present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS and frontotemporal dementia.

Original languageEnglish
Pages (from-to)352-363
Number of pages12
JournalNeurotherapeutics
Volume12
Issue number2
Early online date5 Feb 2015
DOIs
Publication statusPublished - 1 Apr 2015

Keywords

  • ALS
  • C9ORF72
  • FTD
  • Proteinopathy
  • TARDBP
  • TDP

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