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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease classically defined by the impairment of the voluntary motor system and ubiquitin-positive intraneuronal aggregates in anterior horn cells. Frontotemporal dementia (FTD) is a common form of neurodegenerative dementia and presents with personality change associated in a significant subgroup of patients with cortical ubiquitin-only neuropathology (FTD-U). Careful study of ALS as well as FTD patient cohorts suggests clinical as well as pathological overlap of ALS with FTD. The idea that this reflects a shared pathogenesis has received strong support from the identification of new genetic loci on chromosome 9p and of mutations in specific genes (CHMP2B and DCN1) in families with co-segregation of ALS and FTD. The identification of two further genetic causes of FTD-U with (rare) ALS (PGRN) or without ALS (VCP) also provides a starting point for exploring the pathways associated with ubiquitin-mediated protein mishandling in FTD-U and ALS. Pure ALS, through ALS with cognitive impairment and ALS-FTD to pure FTD-U, may represent a continuous spectrum of ubiquitin-associated neurodegenerative disease.

Original publication

DOI

10.1093/hmg/ddl202

Type

Journal article

Journal

Hum Mol Genet

Publication Date

15/10/2006

Volume

15 Spec No 2

Pages

R182 - R187

Keywords

Adenosine Triphosphatases, Amyotrophic Lateral Sclerosis, Cell Cycle Proteins, Dementia, Dynactin Complex, Endosomal Sorting Complexes Required for Transport, Genetic Linkage, Humans, Inclusion Bodies, Intercellular Signaling Peptides and Proteins, Microtubule-Associated Proteins, Nerve Degeneration, Nerve Tissue Proteins, Ubiquitin