Tauopathies microtubules

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). 

Keywords Tau Tauopathy Alzheimer s disease Frontotemporal dementia Parkinsonism Exon Microtubule Structural Protein Phosphorylation... 

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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). 

Zhang B, Maiti A, Shively S, Lakhani F, McDonald-Jones G, Bruce J, Lee EB, Xie SX, Joyce S, Li C, Toleikis PM, Lee VM, Trojanowski JQ. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc. Natl. Acad. Sci. U.S.A. 2005 102 227-231. 

In a Drosophila model of tauopathy in which abnormal human tau mediates neuronal dysfunction characterized by microtubule destabilization, axonal transport disruption, synaptic defects and behavioral impairments, the microtubule-stabilizing drug, NAPVSIPQ (NAP) (davunetide), prevents as well as reverses these phenotypes even after they have become established [341],... 

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