Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Just as neuronal activity is essential to normal brain function, microtubule-associated protein tau appears to be critical to normal neuronal activity in the mammalian brain, especially in the evolutionary most advanced species, the homo sapiens. While the loss of functional tau can be compensated by the other two neuronal microtubule-associated proteins, MAP1A/MAP1B and MAP2, it is the dysfunctional, i.e., the toxic tau, which forces an affected neuron in a long and losing battle resulting in a slow but progressive retrograde neurodegeneration. It is this pathology which is characteristic of Alzheimer disease (AD) and other tauopathies. To date, the most established and the most compelling cause of dysfunctional tau in AD and other tauopathies is the abnormal hyperphosphorylation of tau. The abnormal hyperphosphorylation not only results in the loss of tau function of promoting assembly and stabilizing microtubules but also in a gain of a toxic function whereby the pathological tau sequesters normal tau, MAP1A/MAP1B and MAP2, and causes inhibition and disruption of microtubules. This toxic gain of function of the pathological tau appears to be solely due to its abnormal hyperphosphorylation because dephosphorylation converts it functionally into a normal-like state. The affected neurons battle the toxic tau both by continually synthesizing new normal tau and as well as by packaging the abnormally hyperphosphorylated tau into inert polymers, i.e., neurofibrillary tangles of paired helical filaments, twisted ribbons and straight filaments. Slowly but progressively, the affected neurons undergo a retrograde degeneration. The hyperphosphorylation of tau results both from an imbalance between the activities of tau kinases and tau phosphatases and as well as changes in tau's conformation which affect its interaction with these enzymes. A decrease in the activity of protein phosphatase-2A (PP-2A) in AD brain and certain missense mutations seen in frontotemporal dementia promotes the abnormal hyperphosphorylation of tau. Inhibition of this tau abnormality is one of the most promising therapeutic approaches to AD and other tauopathies.
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PMID:Tau pathology in Alzheimer disease and other tauopathies. 1561 38

Homozygous tau knockout (Mapt-/-) mice develop age-dependent dopaminergic (DA) neuronal loss in the substantia nigra (SN) and ventral tegmental area (VTA), supporting an important function of tau in maintaining the survival of midbrain dopaminergic neurons (mDANs) during aging. However, it remains to be determined whether the microtubule-associated protein tau regulates the differentiation and survival of mDANs during embryonic developmental stages. Here, we show that tau haploinsufficiency in postnatal day 0 (P0) heterozygous (Mapt+/-) pups, but not a complete loss of tau in the Mapt-/- littermates, led to a significant reduction of DA neurons in the VTA. This selective loss of DA neurons correlated with a similar reduction in orthodenticle homeobox 2 (Otx2), which is restricted to VTA neurons at the postmitotic stage and selectively controls the neurogenesis and survival of specific neuronal subtypes of VTA. Moreover, the prenatal developmental cell death in the Mapt+/- VTA specifically increased, and the expression of microtubule-associated protein (MAP)-1A was significantly up-regulated in the P0 Mapt-/- , but not the Mapt+/- , pups. These results suggest that tau haploinsufficiency, without the compensation effect of MAP1A, induces reduction of Otx2 expression, increases prenatal cell death, and accordingly leads to selective loss of VTA DA neurons in the early postnatal stage. Our findings highlight the impact of tau haploinsufficiency on the survival of mDANs and indicate that tau may participate in midbrain development in a dose-dependent way.-Zheng, M., Jiao, L., Tang, X., Xiang, X., Wan, X., Yan, Y., Li, X., Zhang, G., Li, Y., Jiang, B., Cai, H., Lin, X. Tau haploinsufficiency causes prenatal loss of dopaminergic neurons in the ventral tegmental area and reduction of transcription factor orthodenticle homeobox 2 expression.
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PMID:Tau haploinsufficiency causes prenatal loss of dopaminergic neurons in the ventral tegmental area and reduction of transcription factor orthodenticle homeobox 2 expression. 2842 50