title: Tau gene mutations and neurodegeneration.
abstract: Abundant neurofibrillary lesions made of the microtubule-associated protein tau constitute a defining neuropathological characteristic of Alzheimer's disease. Filamentous tau protein deposits are also the defining neuropathological characteristic of other neurodegenerative diseases, many of which are frontotemporal dementias or movement disorders, such as Pick's disease, progressive supranuclear palsy and corticobasal degeneration. It is well established that the distribution of tau pathology correlates with the presence of symptoms of disease. However, until recently, there was no genetic evidence linking dysfunction of tau protein to neurodegeneration and dementia. This has now changed with the discovery of close to 20 mutations in the tau gene in frontotemporal dementia with Parkinsonism linked to chromosome 17. All cases with tau mutations examined to date have shown an abundant filamentous tau pathology in brain cells. Pathological heterogeneity is determined to a large extent by the location of mutations in tau. Known mutations are either coding region or intronic mutations located close to the splice-donor site of the intron downstream of exon 10. Most coding region mutations produce a reduced ability of tau to interact with microtubules. Several of these mutations also promote sulphated glycosaminoglycan-induced assembly of tau into filaments. Intronic mutations and some coding region mutations produce increased splicing in of exon 10, resulting in an overexpression of four-repeat tau isoforms. Thus a normal ratio of three-repeat to four-repeat tau isoforms is essential for preventing the development of tau pathology. The new work has shown that dysfunction of tau protein can cause neurodegeneration and dementia.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, U.K.
authors.forename: M
authors.initials: M
authors.lastname: Goedert
authors.forename: M G
authors.initials: MG
authors.lastname: Spillantini
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D003704:Dementia / Q000150:complications / Q000235:genetics; D006801:Humans; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D020734:Parkinsonian Disorders / Q000150:complications / Q000235:genetics; D016875:tau Proteins / Q000235:genetics*
chemical_list: D016875:tau Proteins