RNA Binding Proteins and the Pathogenesis of Frontotemporal Lobar Degeneration

Annu Rev Pathol. 2019 Jan 24:14:469-495. doi: 10.1146/annurev-pathmechdis-012418-012955. Epub 2018 Oct 24.


Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype-phenotype correlations. Specifically, recent studies have uncovered the unique properties of the low-complexity domains in RNA binding proteins that can facilitate liquid-liquid phase separation in the formation of membraneless organelles. Furthermore, there is compelling evidence that mutations in FTLD genes lead to dysfunction in diverse cellular pathways that converge on the endolysosomal pathway, autophagy, and neuroinflammation. Together, these results provide key mechanistic insights into the pathogenesis and potential therapeutic targets of FTLD.

Keywords: ALS; FTD; FTLD; FUS; RNA binding proteins; TDP-43; amyotrophic lateral sclerosis; frontotemporal dementia; frontotemporal lobar degeneration; hydrogels; liquid droplets; low-complexity domain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis
  • Animals
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Frontotemporal Dementia
  • Frontotemporal Lobar Degeneration / etiology
  • Frontotemporal Lobar Degeneration / genetics
  • Frontotemporal Lobar Degeneration / metabolism*
  • Humans
  • Mutation*
  • RNA-Binding Protein FUS / genetics*
  • RNA-Binding Protein FUS / metabolism
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • TDP-43 Proteinopathies
  • tau Proteins


  • DNA-Binding Proteins
  • FUS protein, human
  • RNA-Binding Protein FUS
  • RNA-Binding Proteins
  • TARDBP protein, human
  • tau Proteins