Alzheimer's Disease (AD) Indeed, the pathology of Aβ and tau in AD is not fully elucidated, it has been implied that intracellular Aβ oligomers have impaired proteasome activity which is contributing to the age-related pathological accumulation of Aβ and tau in the AD mouse model when the levels of Aβ oligomers are elevated (Tseng et al., 2008). Along with Aβ, tau, which is an intrinsically unstructured protein associated with microtubules, is also involved in the pathology of AD (Lee et al., 2013; Selkoe, 2011). Whether the significance of Ub-independent and Ub-dependent degradation of tau within the cell through the UPS and autophagy is contradictory, the accumulation of ubiquitin-positive tau tangle, the association of tau with different subunits of proteasome and identifications of poly-ubiquitinated tau at several K-linkages (K6, K11, K48, and K63 linkages) were suggested for the association of cellular degradation mechanisms in AD (Lee et al., 2013). Parallel to the role of autophagy as a second line of the UPS, it has also been suggested that soluble tau is degraded via the UPS, whereas oligomeric tau aggregates are efficiently degraded via the autophagy-lysosomal system (Kruger et al., 2012; Lee et al., 2013; Wang and Mandelkow, 2012). Post-modification of tau also influences the formation of tau aggregates. Acetylation of tau by the histone acetyl transferase p300 prevents degradation of phosphorylated tau, and conversely, deficiency of the deacetylase SIRT1 increases aggregation levels of acetylated tau (Cohen et al., 2011; Min et al. , 2010). Furthermore, the identification of the Hsp90-CHIP complex that selectively degrades phosphorylated tau proposes the active role of the UPS in the elimination of aberrant tau protein (Dickey et al., 2007; Salminen et al....... half of document .. ...., 2007; Lowe et al., 1990). On the other hand, overexpression of UCHL1 substantially restored learning and memory abilities in AD mice (Gong and Leznik, 2007). Furthermore, a modern molecular genetic analysis finds that novel recessive familial loss of UCHL1 function leads to early-onset progressive neurodegeneration, and this missense mutation within the ubiquitin-binding domain of UCHL1 (E7A) dramatically impairs activity of ubiquitin and hydrolase binding compared to the previous mutation in UHCL1 (I93M) in vitro (Bilguvar et al., 2013). Apparently, mutations of ubiquitin-related proteins (PAKIN and UCHL1) and proteasome disorders, mainly loss of function in the UPS, manifest that the collapse of proteostasis as a consequence of failure to eliminate aberrant proteins, not all but above all it aggravates the pathological situation of many diseases.
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