TY - JOUR
T1 - Reducing synuclein accumulation improves neuronal survival after spinal cord injury
AU - Fogerson, Stephanie M.
AU - van Brummen, Alexandra J.
AU - Busch, David J.
AU - Allen, Scott R.
AU - Roychaudhuri, Robin
AU - Banks, Susan M.L.
AU - Klärner, Frank Gerrit
AU - Schrader, Thomas
AU - Bitan, Gal
AU - Morgan, Jennifer R.
N1 - Funding Information:
This work was supported by research grants from the Morton Cure Paralysis Fund and the NIH (RO1 NS078165 to JRM), a Parkinson''s Disease Foundation summer student fellowship (PDF-SFW-1214 to AJVB), University of California-Los Angeles Jim Easton Consortium for Alzheimer''s Drug Discovery and Biomarker Development (GB), and Team Parkinson/Parkinson Alliance (GB). The authors would like to thank Michele Nsianya and the 2013 Brown-MBL NeuroPracticum Course students for the technical assistance with immunofluorescence experiments, and Paul Oliphint for the histological image of the lamprey spinal cord.
Funding Information:
This work was supported by research grants from the Morton Cure Paralysis Fund and the NIH ( RO1 NS078165 to JRM), a Parkinson's Disease Foundation summer student fellowship ( PDF-SFW-1214 to AJVB), University of California-Los Angeles Jim Easton Consortium for Alzheimer's Drug Discovery and Biomarker Development (GB), and Team Parkinson/Parkinson Alliance (GB). The authors would like to thank Michele Nsianya and the 2013 Brown-MBL NeuroPracticum Course students for the technical assistance with immunofluorescence experiments, and Paul Oliphint for the histological image of the lamprey spinal cord.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - Spinal cord injury causes neuronal death, limiting subsequent regeneration and recovery. Thus, there is a need to develop strategies for improving neuronal survival after injury. Relative to our understanding of axon regeneration, comparatively little is known about the mechanisms that promote the survival of damaged neurons. To address this, we took advantage of lamprey giant reticulospinal neurons whose large size permits detailed examination of post-injury molecular responses at the level of individual, identified cells. We report here that spinal cord injury caused a select subset of giant reticulospinal neurons to accumulate synuclein, a synaptic vesicle-associated protein best known for its atypical aggregation and causal role in neurodegeneration in Parkinson's and other diseases. Post-injury synuclein accumulation took the form of punctate aggregates throughout the somata and occurred selectively in dying neurons, but not in those that survived. In contrast, another synaptic vesicle protein, synaptotagmin, did not accumulate in response to injury. We further show that the post-injury synuclein accumulation was greatly attenuated after single dose application of either the "molecular tweezer" inhibitor, CLR01, or a translation-blocking synuclein morpholino. Consequently, reduction of synuclein accumulation not only improved neuronal survival, but also increased the number of axons in the spinal cord proximal and distal to the lesion. This study is the first to reveal that reducing synuclein accumulation is a novel strategy for improving neuronal survival after spinal cord injury.
AB - Spinal cord injury causes neuronal death, limiting subsequent regeneration and recovery. Thus, there is a need to develop strategies for improving neuronal survival after injury. Relative to our understanding of axon regeneration, comparatively little is known about the mechanisms that promote the survival of damaged neurons. To address this, we took advantage of lamprey giant reticulospinal neurons whose large size permits detailed examination of post-injury molecular responses at the level of individual, identified cells. We report here that spinal cord injury caused a select subset of giant reticulospinal neurons to accumulate synuclein, a synaptic vesicle-associated protein best known for its atypical aggregation and causal role in neurodegeneration in Parkinson's and other diseases. Post-injury synuclein accumulation took the form of punctate aggregates throughout the somata and occurred selectively in dying neurons, but not in those that survived. In contrast, another synaptic vesicle protein, synaptotagmin, did not accumulate in response to injury. We further show that the post-injury synuclein accumulation was greatly attenuated after single dose application of either the "molecular tweezer" inhibitor, CLR01, or a translation-blocking synuclein morpholino. Consequently, reduction of synuclein accumulation not only improved neuronal survival, but also increased the number of axons in the spinal cord proximal and distal to the lesion. This study is the first to reveal that reducing synuclein accumulation is a novel strategy for improving neuronal survival after spinal cord injury.
KW - CLR01
KW - Lamprey
KW - Molecular tweezer
KW - Neurodegeneration
KW - Parkinson's disease
KW - Synaptotagmin
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UR - http://www.scopus.com/inward/citedby.url?scp=84960938200&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2016.02.004
DO - 10.1016/j.expneurol.2016.02.004
M3 - Article
C2 - 26854933
AN - SCOPUS:84960938200
SN - 0014-4886
VL - 278
SP - 105
EP - 115
JO - Experimental Neurology
JF - Experimental Neurology
ER -