Making connections: Pathology and genetics link amyotrophic lateral sclerosis with frontotemporal lobe dementia

Faisal Fecto, Teepu Siddique*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Over the last couple of decades, there has been a growing body of clinical, genetic, and histopathological evidence that similar pathological processes underlie amyotrophic lateral sclerosis (ALS) and some types of frontotemporal lobe dementia (FTD). Even though there is great diversity in the genetic causes of these disorders, there is a high degree of overlap in their histopathology. Genes linked to rare cases of familial ALS and/or FTD, like FUS, TARDBP, OPTN, and UBQLN2 may converge onto a unifying pathogenic pathway and thereby provide novel therapeutic targets common to a spectrum of etiologically diverse forms of ALS and ALS-FTD. Additionally, there are major loci for ALS-FTD on chromosomes 9p and 15q. Identification of causative genetic alterations at those loci will be an important step in understanding the pathogenesis of juvenile- and adult-onset ALS and ALS-FTD. Interactions between TDP-43, FUS, optineurin, and ubiquilin 2 need to be studied to understand their common molecular pathways. Future efforts should also be directed towards generation and characterization of in vivo models to dissect the pathogenic mechanisms of these diseases. Such efforts will rapidly accelerate the discovery of new drugs that regulate accumulation of pathogenic proteins and their downstream consequences.

Original languageEnglish (US)
Pages (from-to)663-675
Number of pages13
JournalJournal of Molecular Neuroscience
Volume45
Issue number3
DOIs
StatePublished - Nov 1 2011

Keywords

  • Amyotrophic lateral sclerosis
  • FALS
  • FTLD-U
  • FUS
  • Frontotemporal lobe dementia
  • Genetics
  • Juvenile ALS
  • Neurodegeneration
  • OPTN
  • Optineurin
  • Parkinsonism
  • Pathology
  • SALS
  • SQSTM1
  • TDP-43
  • UBQLN2
  • Ubiquilin 2
  • Ubiquitinated inclusions
  • p62

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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