AAV2 mediated retrograde transduction of corticospinal motor neurons reveals initial and selective apical dendrite degeneration in ALS

Javier H. Jara; Stephanie R. Villa; Nabil A. Khan; Martha C. Bohn; P. Hande Özdinler

doi:10.1016/j.nbd.2012.03.036

AAV2 mediated retrograde transduction of corticospinal motor neurons reveals initial and selective apical dendrite degeneration in ALS

Javier H. Jara, Stephanie R. Villa, Nabil A. Khan, Martha C. Bohn, P. Hande Özdinler^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

63 Scopus citations

Abstract

Corticospinal motor neurons (CSMN) are the cortical component of motor neuron circuitry, which controls voluntary movement and degenerates in diseases such as amyotrophic lateral sclerosis, primary lateral sclerosis and hereditary spastic paraplegia. By using dual labeling combined with molecular marker analysis, we identified AAV2-2 mediated retrograde transduction as an effective approach to selectively target CSMN without affecting other neuron populations both in wild-type and hSOD1^G93A transgenic ALS mice. This approach reveals very precise details of cytoarchitectural defects within vulnerable neurons in vivo. We report that CSMN vulnerability is marked by selective degeneration of apical dendrites especially in layer II/III of the hSOD1^G93A mouse motor cortex, where cortical input to CSMN function is vastly modulated. While our findings confirm the presence of astrogliosis and microglia activation, they do not lend support to their direct role for the initiation of CSMN vulnerability. This study enables development of targeted gene replacement strategies to CSMN in the cerebral cortex, and reveals CSMN cortical modulation defects as a potential cause of neuronal vulnerability in ALS.

Original language	English (US)
Pages (from-to)	174-183
Number of pages	10
Journal	Neurobiology of Disease
Volume	47
Issue number	2
DOIs	https://doi.org/10.1016/j.nbd.2012.03.036
State	Published - Aug 2012

Funding

This work has been supported by grants from the Les Turner ALS Foundation , Wenske Foundation , Brain Research Foundation (P.H.O), Northwestern University Translational Innovation grant (P.H.O. and M.C.B). J.H.J. was supported by the ALSA Safenowitz postdoctoral fellowship, and S.R.V. by the NIH T32-GM08061 Pre-doctoral training grant. We would like to thank, J. Xie for excellent technical assistance and W. Weber for help with experiments. We would also like to thank B. Goosens from the Microscopy and Imaging Facility at Children's Memorial Research Center for assistance with confocal microscopy. D. Srivastava and P. Penzes helped with initial stages of apical and basal dendrite analysis and generously shared their laboratory resources. NHLBI Gene Therapy Resource Program (GTRP) provided the AAV serotypes.

Keywords

ALS
Corticospinal motor neurons
Gene therapy

ASJC Scopus subject areas

Neurology

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10.1016/j.nbd.2012.03.036

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title = "AAV2 mediated retrograde transduction of corticospinal motor neurons reveals initial and selective apical dendrite degeneration in ALS",

abstract = "Corticospinal motor neurons (CSMN) are the cortical component of motor neuron circuitry, which controls voluntary movement and degenerates in diseases such as amyotrophic lateral sclerosis, primary lateral sclerosis and hereditary spastic paraplegia. By using dual labeling combined with molecular marker analysis, we identified AAV2-2 mediated retrograde transduction as an effective approach to selectively target CSMN without affecting other neuron populations both in wild-type and hSOD1G93A transgenic ALS mice. This approach reveals very precise details of cytoarchitectural defects within vulnerable neurons in vivo. We report that CSMN vulnerability is marked by selective degeneration of apical dendrites especially in layer II/III of the hSOD1G93A mouse motor cortex, where cortical input to CSMN function is vastly modulated. While our findings confirm the presence of astrogliosis and microglia activation, they do not lend support to their direct role for the initiation of CSMN vulnerability. This study enables development of targeted gene replacement strategies to CSMN in the cerebral cortex, and reveals CSMN cortical modulation defects as a potential cause of neuronal vulnerability in ALS.",

keywords = "ALS, Corticospinal motor neurons, Gene therapy",

author = "Jara, {Javier H.} and Villa, {Stephanie R.} and Khan, {Nabil A.} and Bohn, {Martha C.} and {\"O}zdinler, {P. Hande}",

note = "Funding Information: This work has been supported by grants from the Les Turner ALS Foundation , Wenske Foundation , Brain Research Foundation (P.H.O), Northwestern University Translational Innovation grant (P.H.O. and M.C.B). J.H.J. was supported by the ALSA Safenowitz postdoctoral fellowship, and S.R.V. by the NIH T32-GM08061 Pre-doctoral training grant. We would like to thank, J. Xie for excellent technical assistance and W. Weber for help with experiments. We would also like to thank B. Goosens from the Microscopy and Imaging Facility at Children's Memorial Research Center for assistance with confocal microscopy. D. Srivastava and P. Penzes helped with initial stages of apical and basal dendrite analysis and generously shared their laboratory resources. NHLBI Gene Therapy Resource Program (GTRP) provided the AAV serotypes.",

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doi = "10.1016/j.nbd.2012.03.036",

language = "English (US)",

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AU - Khan, Nabil A.

AU - Bohn, Martha C.

AU - Özdinler, P. Hande

N1 - Funding Information: This work has been supported by grants from the Les Turner ALS Foundation , Wenske Foundation , Brain Research Foundation (P.H.O), Northwestern University Translational Innovation grant (P.H.O. and M.C.B). J.H.J. was supported by the ALSA Safenowitz postdoctoral fellowship, and S.R.V. by the NIH T32-GM08061 Pre-doctoral training grant. We would like to thank, J. Xie for excellent technical assistance and W. Weber for help with experiments. We would also like to thank B. Goosens from the Microscopy and Imaging Facility at Children's Memorial Research Center for assistance with confocal microscopy. D. Srivastava and P. Penzes helped with initial stages of apical and basal dendrite analysis and generously shared their laboratory resources. NHLBI Gene Therapy Resource Program (GTRP) provided the AAV serotypes.

PY - 2012/8

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N2 - Corticospinal motor neurons (CSMN) are the cortical component of motor neuron circuitry, which controls voluntary movement and degenerates in diseases such as amyotrophic lateral sclerosis, primary lateral sclerosis and hereditary spastic paraplegia. By using dual labeling combined with molecular marker analysis, we identified AAV2-2 mediated retrograde transduction as an effective approach to selectively target CSMN without affecting other neuron populations both in wild-type and hSOD1G93A transgenic ALS mice. This approach reveals very precise details of cytoarchitectural defects within vulnerable neurons in vivo. We report that CSMN vulnerability is marked by selective degeneration of apical dendrites especially in layer II/III of the hSOD1G93A mouse motor cortex, where cortical input to CSMN function is vastly modulated. While our findings confirm the presence of astrogliosis and microglia activation, they do not lend support to their direct role for the initiation of CSMN vulnerability. This study enables development of targeted gene replacement strategies to CSMN in the cerebral cortex, and reveals CSMN cortical modulation defects as a potential cause of neuronal vulnerability in ALS.

AB - Corticospinal motor neurons (CSMN) are the cortical component of motor neuron circuitry, which controls voluntary movement and degenerates in diseases such as amyotrophic lateral sclerosis, primary lateral sclerosis and hereditary spastic paraplegia. By using dual labeling combined with molecular marker analysis, we identified AAV2-2 mediated retrograde transduction as an effective approach to selectively target CSMN without affecting other neuron populations both in wild-type and hSOD1G93A transgenic ALS mice. This approach reveals very precise details of cytoarchitectural defects within vulnerable neurons in vivo. We report that CSMN vulnerability is marked by selective degeneration of apical dendrites especially in layer II/III of the hSOD1G93A mouse motor cortex, where cortical input to CSMN function is vastly modulated. While our findings confirm the presence of astrogliosis and microglia activation, they do not lend support to their direct role for the initiation of CSMN vulnerability. This study enables development of targeted gene replacement strategies to CSMN in the cerebral cortex, and reveals CSMN cortical modulation defects as a potential cause of neuronal vulnerability in ALS.

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AAV2 mediated retrograde transduction of corticospinal motor neurons reveals initial and selective apical dendrite degeneration in ALS

Abstract

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