Tauopathies

Multiple = system tauopathy Frontotemporal regions, 4R tau NFT in oligodendroglia and... 

Goedert M. Filamentous nerve cell inclusions in neurodegenerative diseases tauopathies and a-synucleinopathies. Philos Trans R Soc Lond B 1999 354 1101-1118. 

NEURODEGENERATIVE a-SYNUCLEINOPATHIES AND TAUOPATHIES 745 NEUROTRANSMITTERS AND DISORDERS OF THE BASAL GANGLIA 761 NEUROBIOLOGY OF ALZHEIMER S DISEASE 781 MOLECULAR BASIS OF PRION DISEASES 791... 

The development of the neurofibrillary pathology is not random 753 SPORADIC TAUOPATHIES 753... 

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). 

Co-expression of human tau with the fly homolog of GSK3-P resulted in accelerated neurodegeneration and the formation of tau-immunoreactive inclusions. In contrast to what has been described in FTDP-17 and mouse models of tauopathies, tau-induced neurodegeneration involved programmed cell death. Taken together, it appears that conformationally altered, nonfilamentous human tau protein is neurotoxic in invertebrates. 

It is now well established that a neurodegenerative pathway leading from soluble to insoluble, filamentous tau protein is central to the neurodegenerative process in the human tauopathies. The availability of animal models that exhibit the essential molecular and cellular features... 

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. 

Wittmann, C.W. et al. Tauopathy in Drosophila Neurodegeneration without neurofibrillary tangles. Science 293, 711-714, 2001. 

Tau pathology in AD is circumscribed to neurons, while in other tauopathies, such as corticobasal degeneration, PSP and familial multiple system tauopathy with presenile dementia, both nerve cells and ghal cells are affected (210,211). PINl binds hyperphosphorylated tau, resulting in depletion of soluble PINl in AD brains. 

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. 

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