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

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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.

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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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  1. Davee Department of Neurology and Clinical Neurosciences, Feinberg School of Medicine, Northwestern University, Tarry Building, Room 13-715, 303 East Chicago Ave., Chicago, IL, 60611, USA

    Faisal Fecto & Teepu Siddique

  2. Interdepartmental Neuroscience Program, Northwestern University, Chicago, IL, 60611, USA

    Faisal Fecto & Teepu Siddique

  3. Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611, USA

    Teepu Siddique

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Fecto, F., Siddique, T. Making Connections: Pathology and Genetics Link Amyotrophic Lateral Sclerosis with Frontotemporal Lobe Dementia. J Mol Neurosci 45, 663–675 (2011). https://doi.org/10.1007/s12031-011-9637-9

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