Making Connections: Pathology and Genetics Link Amyotrophic Lateral Sclerosis with Frontotemporal Lobe Dementia

Article

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.

Keywords

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

Abbreviations

ALS

Amyotrophic lateral sclerosis

FALS

Familial amyotrophic lateral sclerosis

SALS

Sporadic amyotrophic lateral sclerosis

JALS

Juvenile-onset amyotrophic lateral sclerosis

FTD

Frontotemporal lobe dementia

ALS–FTD

Amyotrophic lateral sclerosis with frontotemporal lobe dementia

PDB

Paget disease of the bone

SNP

Single nucleotide polymorphism

GWAS

Genome-wide association study

FTLD

Frontotemporal lobar degeneration

FTLD-U

Frontotemporal lobe dementia with tau-negative, ubiquitin-positive inclusions

FTLD–TDP

Frontotemporal lobe dementia with ubiquitin-positive, TDP-43-positive inclusions

FTLD–FUS

Frontotemporal lobe dementia with ubiquitin-positive, FUS-positive inclusions

SOD1

Cu/Zn superoxide dismutase

TARDBP

TAR DNA binding protein

FUS

Fused in sarcoma

OPTN

Optineurin

SQSTM1

Sequestosome 1

UBQLN2

Ubiquilin 2

VCP

Valosin-containing protein

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Davee Department of Neurology and Clinical Neurosciences, Feinberg School of MedicineNorthwestern UniversityChicagoUSA
  2. 2.Interdepartmental Neuroscience ProgramNorthwestern UniversityChicagoUSA
  3. 3.Department of Cell and Molecular BiologyNorthwestern University, Feinberg School of MedicineChicagoUSA

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