Co-regulation of survival of motor neuron and Bcl-xL expression: Implications for neuroprotection in spinal muscular atrophy

R.S. Anderton; L.L. Price; B.J. Turner; B.P. Meloni; C. Mitrpant; F.L. Mastaglia; C. Goh; S.D. Wilton; S. Boulos

doi:10.1016/j.neuroscience.2012.06.042

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Co-regulation of survival of motor neuron and Bcl-xL expression: Implications for neuroprotection in spinal muscular atrophy

Journal article

Peer reviewed

Co-regulation of survival of motor neuron and Bcl-xL expression: Implications for neuroprotection in spinal muscular atrophy

R.S. Anderton, L.L. Price, B.J. Turner, B.P. Meloni, C. Mitrpant, F.L. Mastaglia, C. Goh, S.D. Wilton and S. Boulos

Neuroscience, Vol.220, pp.228-236

2012

DOI: https://doi.org/10.1016/j.neuroscience.2012.06.042

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Abstract

Spinal muscular atrophy (SMA), a fatal genetic motor disorder of infants, is caused by diminished full-length survival of motor neuron (SMN) protein levels. Normally involved in small nuclear ribonucleoprotein (snRNP) assembly and pre-mRNA splicing, recent studies suggest that SMN plays a critical role in regulating apoptosis. Interestingly, the anti-apoptotic Bcl-x isoform, Bcl-xL, is reduced in SMA. In a related finding, Sam68, an RNA-binding protein, was found to modulate splicing of SMN and Bcl-xL transcripts, promoting SMNΔ7 and pro-apoptotic Bcl-xS transcripts. Here we demonstrate that Bcl-xL expression increases SMN protein by ∼2-fold in SH-SY5Y cells. Conversely, SMN expression increases Bcl-xL protein levels by ∼6-fold in SH-SY5Y cells, and ∼2.5-fold in the brains of transgenic mice over-expressing SMN (PrP-SMN). Moreover, Sam68 protein levels were markedly reduced following SMN and Bcl-xL expression in SH-SY5Y cells, suggesting a feedback mechanism co-regulating levels of both proteins. We also found that exogenous SMN expression increased full-length SMN transcripts, possibly by promoting exon 7 inclusion. Finally, co-expression of SMN and Bcl-xL produced an additive anti-apoptotic effect following PI3-kinase inhibition in SH-SY5Y cells. Our findings implicate Bcl-xL as another potential target in SMA therapeutics, and indicate that therapeutic increases in SMN may arise from modest increases in total SMN.

Details

Title: Co-regulation of survival of motor neuron and Bcl-xL expression: Implications for neuroprotection in spinal muscular atrophy
Authors/Creators: R.S. Anderton (Author/Creator) - The University of Western Australia
L.L. Price (Author/Creator) - The University of Western Australia
B.J. Turner (Author/Creator) - Florey Institute of Neuroscience and Mental Health
B.P. Meloni (Author/Creator) - The University of Western Australia
C. Mitrpant (Author/Creator) - The University of Western Australia
F.L. Mastaglia (Author/Creator) - The University of Western Australia
C. Goh (Author/Creator) - The University of Western Australia
S.D. Wilton (Author/Creator) - The University of Western Australia
S. Boulos (Author/Creator) - The University of Western Australia
Publication Details: Neuroscience, Vol.220, pp.228-236
Publisher: Elsevier BV
Identifiers: 991005540246807891
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.255 Musculoskeletal Disorders; 1.255.2204 Spinal Muscular Atrophy
Web Of Science research areas: Neurosciences
ESI research areas: Neuroscience & Behavior