PTEN depletion rescues axonal growth defect and improves survival in SMN-deficient motor neurons.
Phosphatase and tensin homolog (PTEN), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, is widely involved in the regulation of protein synthesis. Here we show that the PTEN protein is enriched in cell bodies and axon terminals of purified motor neurons. We explored the role of the PTEN pathway by manipulating PTEN expression in healthy and diseased motor neurons. PTEN depletion led to an increase in growth cone size, promotion of axonal elongation and increased survival of these cells. These changes were associated with alterations of downstream signaling pathways for local protein synthesis as revealed by an increase in pAKT and p70S6. Most notably, this treatment also restores beta-actin protein levels in axonal growth cones of SMN-deficient motor neurons. Furthermore, we report here that a single injection of adeno-associated virus serotype 6 (AAV6) expressing siPTEN into hind limb muscles at postnatal day 1 in SMNDelta7 mice leads to a significant PTEN depletion and robust improvement in motor neuron survival. Taken together, these data indicate that PTEN-mediated regulation of protein synthesis in motor neurons could represent a target for therapy in spinal muscular atrophy.
Academic Neurology Unit, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield S10 2RX, UK.
Ke
K
Ning
Carsten
C
Drepper
Chiara F
CF
Valori
Mansoor
M
Ahsan
Matthew
M
Wyles
Adrian
A
Higginbottom
Thomas
T
Herrmann
Pamela
P
Shaw
Mimoun
M
Azzouz
Michael
M
Sendtner
D000199:Actins / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology*; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D020439:Growth Cones / Q000378:metabolism; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases
D000199:Actins; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D055533:Survival of Motor Neuron 1 Protein; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase