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



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.


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 



Amyotrophic lateral sclerosis


Familial amyotrophic lateral sclerosis


Sporadic amyotrophic lateral sclerosis


Juvenile-onset amyotrophic lateral sclerosis


Frontotemporal lobe dementia


Amyotrophic lateral sclerosis with frontotemporal lobe dementia


Paget disease of the bone


Single nucleotide polymorphism


Genome-wide association study


Frontotemporal lobar degeneration


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


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


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


Cu/Zn superoxide dismutase


TAR DNA binding protein


Fused in sarcoma




Sequestosome 1


Ubiquilin 2


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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