title: Recent advances in the genetics of amyotrophic lateral sclerosis and frontotemporal dementia: common pathways in neurodegenerative disease.
abstract: 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.
authors.affiliation: Department of Physiology, Anatomy and Genetics , University of Oxford, Henry Wellcome Building of Gene Function, South Parks Road, Oxford OX1 3QX, UK. kevin.talbot@clneuro.ox.ac.uk
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
authors.forename: Olaf
authors.initials: O
authors.lastname: Ansorge
mesh_terms: D000251:Adenosine Triphosphatases; D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D003704:Dementia / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000072159:Dynactin Complex; D056827:Endosomal Sorting Complexes Required for Transport; D008040:Genetic Linkage; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D000077153:Progranulins; D025801:Ubiquitin / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: C503812:CHMP2B protein, human; D018797:Cell Cycle Proteins; D000072159:Dynactin Complex; D056827:Endosomal Sorting Complexes Required for Transport; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D000077153:Progranulins; D025801:Ubiquitin; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein