Tauopathies mutations

Lewy bodies, neurofibrillary lesions and Pick bodies are intracellular filamentous inclusions. It is now well established that Lewy bodies are made of the protein a-synuclein and both neurofibrillary lesions and Pick bodies of the microtubule-associated protein tau. Mutations in the a-synuclein gene or an increase in its copy number cause autosomal-dominantly inherited forms of Parkinson s disease and dementia with Lewy bodies. Mutations in the tau gene cause a familial form of frontotemporal dementia. Here we review the evidence implicating a-synuclein and tau in these inherited and a number of sporadic neurodegenerative diseases. Collectively, a-synucleinopathies and tauopathies account for the vast majority of cases of late-onset neurodegenerative disease (Tables 45-1 and 45-2). 

Spillantini, M.G. et al. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 95 7737-7741,1998. 

Mutations that stimulate exon 10 inclusion into the human tau mRNA, which is regulated by an intricate interplay of cis elements and trans factors, cause FTDP-17 and other tauopathies. This suggests that the ratio of exon 10 inclusion to exclusion in the adult brain is one of the factors to determine biological functions of the tau protein. 

Goedert, M. and Jakes, R (2005) Mutations causing neurodegenerative tauopathies. Biochim Biophys Acta 1739, 240-250. 

Tauopathies are a group of disorders that are the consequence of abnormal tau phosphorylation, abnormal levels of tau, abnormal tau splicing, or mutations in the tau gene. These disorders are characterized not only by neuronal, but also oligo-dendroglial and astrocytic filamentous tau inclusions (Avila, 2000 Ulloa et al.,... 

Snowden JS, Neary D, Mann DM (2002) Frontotemporal dementia. Br J Psychiatry 180 140-143 Sontag E, Nunbhakdi-Craig V, Lee G, Brandt R, Kamibayashi C, Kuret J, et al. (1999) Molecular interactions among protein phosphatase 2A, tau, and microtubules. Imphcations for the regulation of tau phosphorylation and the development of tauopathies. J Biol Chem 274 25490-25498 SpUlantini MG, Goedert M (2000) Tau mutations in familial frontotemporal dementia. Brain 123(Pt 5) 857-859... 

Dynamic microtubules are important not only in dividing cells but also in terminally differentiated cells. For example, they play crucial roles both in the post mitotic development of neurons and in mature neurons such as in the formation of functional neuronal networks and the correct arborization (branching) of dendrites (30). Misregulation of microtubule dynamics, as for example caused by mutations in the neuronal MAP tau, can lead to microtubules whose dynamics fall outside the normally permissible range thus possibly contributing to neurodegeneration in tauopathies such as Alzheimer s disease and FTDP-17 (Fronto-Temporal Dementia with Parkinsonism associated with Chromosome 17) (see Reference 31) (see below). 

---