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J Clin Invest. 2018 Jul 2;128(7):3008-3023. doi: 10.1172/JCI95231. Epub 2018 Jun 11.

Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes.

Author information

1
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
2
Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.
3
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
4
Howard Hughes Medical Institute, Boston, Massachusetts, USA.
5
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.

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.

KEYWORDS:

Autophagy; Molecular biology; Neurodegeneration; Neuroscience; Stem cells

PMID:
29672276
PMCID:
PMC6025996
DOI:
10.1172/JCI95231
[Indexed for MEDLINE]
Free PMC Article

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