PMID:25466238

Citation	Zhang, M, Cai, F, Zhang, S, Zhang, S and Song, W (2014) Overexpression of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) delays Alzheimer's progression in vivo. Sci Rep 4:7298
Abstract	Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). Aβ is produced by β- and γ-cleavages of amyloid β precursor protein (APP). Ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme that cleaves ubiquitin at its carboxyl terminal. Dysfunction of UCHL1 has been reported in neurodegenerative diseases. However, whether UCHL1 affects Aβ production and AD progression remains unknown. Here we report that UCHL1 interacts with APP and regulates Aβ production. UCHL1 increases free ubiquitin level and accelerates the lysosomal degradation of APP by promoting its ubiquitination. Furthermore, we demonstrate that overexpression of UCHL1 by intracranial injection of UCHL1-expressing rAAV reduces Aβ production, inhibits neuritic plaque formation and improves memory deficits in AD transgenic model mice. Our study suggests that UCHL1 may delay Alzheimer's progression by regulating APP degradation in a long-term fashion, and that overexpression of UCHL1 may be a safe and effective disease-modifying strategy to treat AD.
Links	PubMed PMC4252905 Online version:10.1038/srep07298
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:UCHL1		GO:0042985: negative regulation of amyloid precursor protein biosynthetic process	ECO:0000314:		P		Figure 2 shows UCHL 1 reduces the level of mature APP protein	complete CACAO 10616
MOUSE:UCHL1		GO:0042984: regulation of amyloid precursor protein biosynthetic process	ECO:0000314:		P		Figure 1 shows UCHL 1 regulates APP processing	complete CACAO 10617

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