Lys203 and Lys382 are Essential for the Proteasomal Degradation of BACE1

Author(s): Rong Wang, Zhengxin Ying, Juan Zhao, Yanyan Zhang, Ran Wang, Hong Lu, Yulin Deng, Weihong Song3,* and, Weihong Song, Hong Qing.

Journal Name: Current Alzheimer Research

Volume 9 , Issue 5 , 2012

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Abstract:

Amyloid β protein (Aβ) is the primary component of senile plaques in Alzheimer’s disease brains and its aggregate form is neurotoxic. Aβ is generated through proteolysis of β-amyloid precursor protein (APP) by two proteases: β-secretase and γ-secretase. BACE1, the β-secretase in vivo and the key rate-limiting enzyme that initiates the formation of Aβ, is an attractive drug target for AD therapy. Our previous study demonstrated that BACE1 is ubiquitinated and its degradation and effect on APP cleaving process are mediated by the ubiquitin-proteasome pathway. However, the specific underlying mechanism is still not well defined. In present study, we determined the specific binding sites responsible for the proteasomal degradation of BACE1. Ten fragments of human BACE1 cDNA with each of them containing 1 to 3 Lys codons were cloned, and HEK293 cells transfected with these recombinant plasmids were treated with specific proteasome inhibitor lactacystin. The protein levels of fragment-3 (Pro149-Leu180), -4 (IIe179-Ser230) and -8 (Met349-Arg400) were significantly increased by lactacystin treatment, and immunocytochemical staining results showed that fragment-3, -4 and -8 proteins were colocalized with ubiquitin. Site-directed mutagenesis at Lys203 and Lys382 of BACE1 abolished the proteasomal degradation of BACE1 and affected APP processing at β site and Aβ production. Taken together, our study demonstrated that BACE1 Lys203 and Lys382 are essential for its proteasomal degradation, and the results may advance our understanding of regulation of BACE1 and APP processing by the ubiquitin proteasome system in AD pathogenesis and shed new insights on its pharmaceutical potential.

Keywords: APP, BACE1, ubiquitination, Alzheimer.

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Article Details

VOLUME: 9
ISSUE: 5
Year: 2012
Page: [606 - 615]
Pages: 10
DOI: 10.2174/156720512800618026
Price: $58

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