UBE3A and Alzheimer disease: Several prevailing hypotheses exist to explain the elevation of poly-Ub in AD brains: (1) downregulation of β5 (135); (2) aggregated and accumulated forms of AD-associated proteins (Tau and Aβ) inhibiting proteasome activity (33, 37, 124, 127, 130, 136); and (3) impairment of E3 ligases (such as CHIP, UCHL1, Ube3A, Parkin) in AD (136, 137, 138).