The ubiquitin proteasome system and molecular chaperone deregulation in Alzheimer’s disease

Cover-Figure_Heese

The factors involved in the development of Alzheimer’s disease (AD) neuropathology. In the Tau-hypothesis, activation of cellular kinases may phosphorylate Tau, which subsequently causes Tau to lose its affinity to the microtubule system and thus forming aggregates. As an important protein for the microtubule architecture, loss-of-function of Tau in neuronal axons may disrupt the fast axonal transport (FAT), which is imperative in the vesicular transport of neurotransmitters and synapse maintenance. However, the dephosphorylation of Tau can restore its binding to microtubules, therefore negating the effects of Tau-targeting kinases. Tau aggregates act as seed for further aggregation and transmission of such aggregates to surrounding neurons as prion-like proteins. E3 ligases are the enzymes that target Tau for proteasomal degradation and a defense mechanism against prion-like protein transmission. Impaired E3 ligases leads to a defective defensive mechanism against protein aggregation. However, it has been suggested that Tau can be targeted by other E3 ligases, which may act as compensational ligases for targeting Tau for degradation. FK506 binding proteins (FKBPs) expression is another possible risk for promoting Tau aggregation. FKBPs have been reported to be co-localized with Tau and can prevent the degradation of Tau by acting as Tau-stabilizing chaperones; therefore, FKBP inhibitors may nullify the negative effect of FKBPs by preventing Tau binding FKBPs. Familial AD is commonly caused by the mutation in the amyloid precursor protein (APP) or presinilin (PS) gene. The mutation in these genes result in the increased production of the amyloid beta peptide (Aβ) or aberrant APP intracellular domain (AICD) signaling. Aβ and AICD may promote Tau aggregation by activating Tau-kinases, inhibiting Tau proteasomal degradation, or overexpression of FKBPs. Familial AD mutations are great risk factors for the development of AD neuropathology, however, not essential.

Reference:

The Ubiquitin-Proteasome System and Molecular Chaperone Deregulation in Alzheimer’s Disease.
Sulistio YA, Heese K.
Mol Neurobiol. 2015 Jan 7. [Epub ahead of print]

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