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Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes
Natalia Rodriguez-Muela, … , Rajat Singh, Lee L. Rubin
Natalia Rodriguez-Muela, … , Rajat Singh, Lee L. Rubin
Published April 19, 2018
Citation Information: J Clin Invest. 2018;128(7):3008-3023. https://doi.org/10.1172/JCI95231.
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Research Article Neuroscience Stem cells

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

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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.

Authors

Natalia Rodriguez-Muela, Andrey Parkhitko, Tobias Grass, Rebecca M. Gibbs, Erika M. Norabuena, Norbert Perrimon, Rajat Singh, Lee L. Rubin

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Figure 3

p62 interacts with SMN.

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p62 interacts with SMN.
(A) HA and Myc representative IP from HEK293T ly...
(A) HA and Myc representative IP from HEK293T lysates transfected with the indicated plasmids and immunoblotted against HA, Myc, and p62. WB, Western blot. (B) Representative IP of endogenous SMN protein from mouse SMA MN lysates treated with control or SA for 6 hours and immunoblotted against p62, SMN, LC3, and actin. (C) Representative image from mouse SMA ESC–derived MNs cultured in control conditions or with SA and immunostained against p62 (cyan) and SMN (red) (MNs express Hb9:GFP, and nuclei are stained with DAPI, blue). Scale bar: 10 μm. (D) Representative IP of endogenous SMN protein from WT and SMA mouse MNs. (E) MN lysates infected with lentivirus expressing the DN form of Cul5 for 5 days compared with empty vector–infected cells. MN cultures were treated with control media or SA (10 or 50 μM) for the last 6 hours of the culture. Membranes were immunoblotted against ubiquitin, p62, SMN, and actin. HC, heavy IgG chain; LC, light IgG chain.
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