TY - JOUR
T1 - Blocking p62-dependent SMN degradation ameliorates spinal muscular atrophy disease phenotypes
AU - Rodriguez-Muela, Natalia
AU - Parkhitko, Andrey
AU - Grass, Tobias
AU - Gibbs, Rebecca M.
AU - Norabuena, Erika M.
AU - Perrimon, Norbert
AU - Singh, Rajat
AU - Rubin, Lee L.
N1 - Publisher Copyright:
© 2018 American Society for Clinical Investigation. All rights reserved.
PY - 2018/7/2
Y1 - 2018/7/2
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI95231
DO - 10.1172/JCI95231
M3 - Article
C2 - 29672276
AN - SCOPUS:85049855252
SN - 0021-9738
VL - 128
SP - 3008
EP - 3023
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -