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J Clin Invest DOI:10.1172/JCI95231

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

Publication TypeJournal Article
Year of Publication2018
AuthorsRodriguez-Muela, N, Parkhitko, A, Grass, T, Gibbs, RM, Norabuena, EM, Perrimon, N, Singh, R, Rubin, LL
JournalJ Clin Invest
Date Published2018 Jul 02

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.


Alternate JournalJ. Clin. Invest.
PubMed ID29672276
PubMed Central IDPMC6025996
Grant ListP01 NS066888 / NS / NINDS NIH HHS / United States
R01 AG043517 / AG / NIA NIH HHS / United States
R01 AR057352 / AR / NIAMS NIH HHS / United States
P01 AG031782 / AG / NIA NIH HHS / United States
R01 GM084947 / GM / NIGMS NIH HHS / United States