These findings would suggest that contrary to the prevailing view, genetic risk factors for neurodegenerative diseases at the MAPT locus are likely to operate by changing mRNA splicing in different brain regions, as opposed to the overall expression of the MAPT gene.
FTLD is a genetically complex neurodegenerative disorder with mutations in the PGRN and the microtubule-associated protein tau (MAPT) genes being the most common known causes of familial FTLD.
This study sought to determine the nature and frequency of tau gene mutations in an affected proband cohort of patients within this spectrum of neurodegenerative diseases.
Mutations in the microtubule-associated protein tau gene have been linked to neurofibrillary tangle (NFT) formation in several neurodegenerative diseases known as tauopathies; however, no tau mutations occur in Alzheimer's disease, although this disease is also characterized by NFT formation and cell death.
Mutations in the microtubule associated protein tau (MAPT) and progranulin (PGRN) have been identified in several neurodegenerative disorders, such as frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS).
These data provide both the first genetic evidence and functional studies supporting the role of MAPTp.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
Progressive supranuclear palsy (PSP) is a tau deposition neurodegenerative disorder which usually occurs in sporadic form and is associated with a common variant of the tau gene.
Pathological brain inclusions comprised of alpha-synuclein or tau proteins are associated with a spectrum of neurodegenerative disorders, and oxidative and nitrative injury has been implicated in all of these diseases.
Frontotemporal dementia is commonly associated with parkinsonism in several sporadic (i.e., progressive supranuclear palsy, corticobasal degeneration) and familial neurodegenerative disorders (i.e., frontotemporal dementia associated with parkinsonism and MAPT or progranulin mutations in chromosome 17).
Mutations in the microtubule-associated protein tau (MAPT) underlie multiple neurodegenerative disorders, yet the pathophysiological mechanisms are unclear.
Pathologic modifications of the Tau protein leading to neurofibrillary tangle (NFT) formation are a common feature of a wide range of neurodegenerative diseases known as tauopathies, which include Alzheimer's disease (AD).
In addition, Tau gene mutations, aberrant mRNA splicing and abnormal post-translational modifications, such as hyperphosphorylation, lead to formation of pathological, insoluble Tau aggregates that are a hallmark of neurodegenerative diseases, collectively known as tauopathies.
Hereditary frontotemporal dementia (FTD) is an autosomal dominant neurodegenerative disorder that is associated with mutations in the tau gene and with the pathological accumulation of hyperphosphorylated tau protein in affected brain cells in about a quarter of cases.
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is an autosomal dominant neurodegenerative disorder caused by mutations in the MAPT gene which encodes the microtubule-associated protein tau.
We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration.
The microtubule-associated protein tauV363I variation could be considered either an incomplete penetrant mutation or a rare polymorphism; although its pathogenicity has yet to be clearly demonstrated, modifier genetic factors seem to contribute to the pathogenic effects observed in the patient underlining the great complexity existing in neurodegenerative diseases and questioning so-called sporadic cases that can potentially be caused by gene mutation.