期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 128, 期 7, 页码 3008-3023出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI95231
关键词
-
资金
- Muscular Dystrophy Association [MDA376743]
- SMA Foundation
- National Institute of Neurological Disorders and Stroke (NINDS) [P01NS066888]
- National Institute of General Medical Sciences [R01-AG043517, R01-GM084947]
- LAM Foundation Fellowship Award [LAM00105E01-15]
Spinal muscular atrophy (SMA), a degenerative motor neuron (MN) disease, caused by loss of functional survival of motor neuron (SMN) protein due to SMN1 gene mutations, is a leading cause of infant mortality. Increasing SMN levels ameliorates the disease phenotype and is unanimously accepted as a therapeutic approach for patients with SMA. The ubiquitin/proteasome system is known to regulate SMN protein levels; however, whether autophagy controls SMN levels remains poorly explored. Here, we show that SMN protein is degraded by autophagy. Pharmacological and genetic inhibition of autophagy increases SMN levels, while induction of autophagy decreases these levels. SMN degradation occurs via its interaction with the autophagy adapter p62 (also known as SQSTM1). We also show that SMA neurons display reduced autophagosome clearance, increased p62 and ubiquitinated proteins levels, and hyperactivated mTORC1 signaling. Importantly, reducing p62 levels markedly increases SMN and its binding partner gemin2, promotes MN survival, and extends lifespan in fly and mouse SMA models, revealing p62 as a potential new therapeutic target for the treatment of SMA.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据