Targets and Small Molecules Against Tauopathies. Part 1: From Genes to Soluble, Aggregation-Prone Tau Proteins
Pp. 643-715 (73)
Tau is a key dynamic regulator of microtubules in neurons. Tau-microtubule
binding contributes to axonal stabilization in neurons. Its controlled-physiological
weakening allows cell division and microtubule reorganization in fetal state or in
mitotic neuronal cells. Tauopathies often show a decreased tau-microtubule binding and
the aggregation of tau. The former leads to chronic microtubule-axonal destabilization,
the latter preludes to the formation of intra-neuronal, insoluble tau deposits. Tau
alternative splicing and post-translational modifications (hyper-phosphorylation,
glycosylation, prolylamide bond isomerization, oxidation, etc.) are early events with an
impact on tauopathies which may lead to disease-modifying therapeutic interventions.
The most prospective therapeutic avenues targeted against these events are presented
and critically discussed, selecting a single molecular target of particular relevance. Each
target is presented together with its known small molecule modulators. Priority is given
to mechanisms, targets and small molecules impacting on more than one tauopathycausing
Alternative splicing, Alzheimer’s disease, DAPK, DYRK1A, glycosyl
ation, GSK3, kinases, microtubules, neurodegeneration, O-glcnac hydrolase, peptidylprolyl
isomerases, PIN1, post-translational modifications, TAU protein, tauopathies.
Department of Chemistry, University of Milan, Via Golgi 19, I-20133 Milan, Italy.