Cyclin-G-associated kinase GAK/Aux orchestrates glial autophagy via Atg9 phosphorylation in Parkinson's disease

doi:10.1101/2021.08.16.456579

	Cyclin-G-associated kinase GAK/Aux orchestrates glial autophagy via Atg9 phosphorylation in Parkinson's disease
	Zhang, S.1; Wang, L.1 ; Yi, S.1; Li, S.1 ; Wang, H.1 ; Song, L.; Ou, J.2; Zhang, M.1 ; Wang, M.1 ; Zheng, Y.1 ; Wang, R.1 ; Yang, K.4; Liu, T.3; Yan, W.5,6; Liu, C.5,6; Ho, M. S.1
	2021-08-19
状态	已发表
摘要	Glia serve as double-edged swords to modulate neuropathology in Parkinsons disease (PD), but how they react opposingly to be beneficial or detrimental under pathological conditions, like promote or eliminate -Synuclein inclusions, remain elusive. Here we present evidence that the PD risk factor Cyclin G-associated kinase (GAK)/dAuxilin (Aux) is a new component in glial autophagy. Lack of GAK/Aux promotes autophagic induction, disrupts lysosome acidification, and blocks glial clearance of substrates. Aux regulates Atg9 trafficking to autophagosomes and lysosomes for autophagosome biogenesis and autolysosome maturation, respectively, via Atg9 phosphorylation at newly identified residues T62 and T69. GAK/Aux-mediated glial autophagy is required for -Syn degradation and contributes to a broad spectrum of parkinsonian symptoms in Drosophila and mice. Our findings indicate that glial autophagy is a critical component in PD progression and identify a new autophagy factor functioning in a tissue-specific manner; targeting glial autophagy is potentially a therapeutic solution for PD.
关键词	Autophagy Glia Parkinson’s disease GAK dauxilin
语种	英语
DOI	10.1101/2021.08.16.456579
相关网址	查看原文
出处	bioRxiv
收录类别	PPRN.PPRN
WOS记录号	PPRN:14777274
WOS类目	Neurosciences
资助项目	ShanghaiTech["ZDSYS20190902093601675","2020A1515011055","31871039"] ; National Natural Science Foundation of China[32071009]
文献类型	预印本
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/348484
专题	生命科学与技术学院生命科学与技术学院_PI研究组_何淑君组生命科学与技术学院_硕士生生命科学与技术学院_博士生
通讯作者	Ho, M. S.
作者单位	1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 2.Tongji Univ Sch Med, Dept Anat & Neurobiol, Shanghai 200092, Peoples R China 3.Beijing Normal Univ Zhuhai, Adv Inst Nat Sci, Int Acad Ctr Complex Syst, Beijing 519087, Peoples R China 4.Beijing Normal Univ Zhuhai, Adv Inst Nat Sci, Int Acad Ctr Complex Syst, Beijing 519087, Peoples R China 5.Guangdong Prov Key Lab Brain Connectome & Behav, Brain Cognit, CAS Key1 Lab Brain Connectome & Manipulat, Beijing, Peoples R China 6.Chinese Acad Sci, Brain Dis Inst BCBDI, Shenzhen Inst Adv Technol, Shenzhen Hong Kong Inst Brain Sci Shenzhen, Shenzhen, Peoples R China
推荐引用方式 GB/T 7714	Zhang, S.,Wang, L.,Yi, S.,et al. Cyclin-G-associated kinase GAK/Aux orchestrates glial autophagy via Atg9 phosphorylation in Parkinson's disease. 2021.