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Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2018 Jul 02; Vol. 128 (7), pp. 3008-3023. Date of Electronic Publication: 2018 Jun 11. - Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- Animals
Autophagy
Cells, Cultured
Disease Models, Animal
Gene Knockdown Techniques
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
Mice, Knockout
Motor Neurons metabolism
Muscular Atrophy, Spinal pathology
Mutation
Phenotype
Proteolysis
RNA, Small Interfering genetics
SMN Complex Proteins deficiency
SMN Complex Proteins genetics
Sequestosome-1 Protein genetics
Sequestosome-1 Protein metabolism
Survival of Motor Neuron 1 Protein antagonists & inhibitors
Survival of Motor Neuron 1 Protein genetics
Survival of Motor Neuron 1 Protein metabolism
TOR Serine-Threonine Kinases metabolism
Muscular Atrophy, Spinal drug therapy
Muscular Atrophy, Spinal metabolism
SMN Complex Proteins metabolism
Sequestosome-1 Protein antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 128
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 29672276
- Full Text :
- https://doi.org/10.1172/JCI95231