CHIP modulates APP-induced autophagy-dependent pathological symptoms in Drosophila

Luming Zhuang; Fei Peng; Yuanyuan Huang; Wenzhe Li; Jiuhong Huang; Yunqiang Chu; Pu Ren; Ying Sun; Yan Zhang; Elleen Xue; Xiaowei Guo; Xiafeng Shen; Lei Xue

doi:10.1111/acel.13070

CHIP modulates APP-induced autophagy-dependent pathological symptoms in Drosophila

Aging Cell. 2020 Feb;19(2):e13070. doi: 10.1111/acel.13070. Epub 2019 Nov 28.

Authors

Luming Zhuang¹, Fei Peng¹, Yuanyuan Huang¹, Wenzhe Li¹, Jiuhong Huang², Yunqiang Chu¹, Pu Ren¹, Ying Sun¹, Yan Zhang¹, Elleen Xue³, Xiaowei Guo¹, Xiafeng Shen¹, Lei Xue¹

Affiliations

¹ The First Rehabilitation Hospital of Shanghai, Shanghai Key Laboratory of Signaling and Diseases Research, School of Life Science and Technology, Tongji University, Shanghai, China.
² International Academy of Targeted Therapeutics and Innovation, Chongqing University of Arts and Sciences, Chongqing, China.
³ Blair Academy, Blairstown, NJ, USA.

Abstract

Dysregulation of autophagy is associated with the neurodegenerative processes in Alzheimer's disease (AD), yet it remains controversial whether autophagy is a cause or consequence of AD. We have previously expressed the full-length human APP in Drosophila and established a fly AD model that exhibits multiple AD-like symptoms. Here we report that depletion of CHIP effectively palliated APP-induced pathological symptoms, including morphological, behavioral, and cognitive defects. Mechanistically, CHIP is required for APP-induced autophagy dysfunction, which promotes Aβ production via increased expression of BACE and Psn. Our findings suggest that aberrant autophagy is not only a consequence of abnormal APP activity, but also contributes to dysregulated APP metabolism and subsequent AD pathogenesis.

Keywords: CHIP; APP; Alzheimer’s disease; Aβ; autophagy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / metabolism*
Alzheimer Disease / pathology
Amyloid beta-Protein Precursor / genetics
Amyloid beta-Protein Precursor / metabolism*
Amyloid beta-Protein Precursor / toxicity
Animals
Aspartic Acid Endopeptidases / metabolism
Autophagy / genetics*
Brain / metabolism
Cognitive Dysfunction / genetics
Disease Models, Animal
Dopaminergic Neurons / metabolism
Down-Regulation
Drosophila / metabolism*
Drosophila Proteins / genetics
Drosophila Proteins / metabolism*
Eye / growth & development
Eye / metabolism
Learning Disabilities / genetics
Locomotion / genetics
Longevity / genetics
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Presenilins / metabolism
RNA Interference
Wings, Animal / metabolism
Wings, Animal / pathology

Substances

Amyloid beta-Protein Precursor
Chi protein, Drosophila
Drosophila Proteins
Nuclear Proteins
Presenilins
Psn protein, Drosophila
Aspartic Acid Endopeptidases
Bace protein, Drosophila

Abstract

Publication types

MeSH terms

Substances

Grants and funding