BACE1 SUMOylation increases its stability and escalates the protease activity in Alzheimer’s disease

Amyloid beta (Aβ) is a major pathological marker in Alzheimer’s disease (AD), which is principally regulated by the rate-limiting β-secretase (i.e., BACE1) cleavage of amyloid precursor protein (APP). However, how BACE1 activity is posttranslationally regulated remains incompletely understood. Here,...

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Detalles Bibliográficos
Autores principales: Bao, Jian, Qin, Min, Mahaman, Yacoubou Abdoul Razak, Zhang, Bin, Huang, Fang, Zeng, Kuan, Xia, Yiyuan, Ke, Dan, Wang, Qun, Liu, Rong, Wang, Jian-Zhi, Ye, Keqiang, Wang, Xiaochuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899489/
https://www.ncbi.nlm.nih.gov/pubmed/29581300
http://dx.doi.org/10.1073/pnas.1800498115
Descripción
Sumario:Amyloid beta (Aβ) is a major pathological marker in Alzheimer’s disease (AD), which is principally regulated by the rate-limiting β-secretase (i.e., BACE1) cleavage of amyloid precursor protein (APP). However, how BACE1 activity is posttranslationally regulated remains incompletely understood. Here, we show that BACE1 is predominantly SUMOylated at K501 residue, which escalates its protease activity and stability and subsequently increases Aβ production, leading to cognitive defect seen in the AD mouse model. Compared with a non-SUMOylated K501R mutant, injection of wild-type BACE1 significantly increases Aβ production and triggers cognitive dysfunction. Furthermore, overexpression of wild-type BACE1, but not non-SUMOylated K501R mutant, facilitates senile plaque formation and aggravates the cognitive deficit seen in the APP/PS1 AD mouse model. Together, our data strongly suggest that K501 SUMOylation on BACE1 plays a critical role in mediating its stability and enzymatic activity.