Selective forelimb impairment in rats expressing a pathological TDP-43 25 kDa C-terminal fragment to mimic amyotrophic lateral sclerosis

Robert D. Dayton, Michael A. Gitcho, Elysse A. Orchard, Jon D. Wilson, David B. Wang, Cooper D. Cain, Jeffrey A. Johnson, Yong Jie Zhang, Leonard Petrucelli, James Michael Mathis, Ronald L. Klein

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Abstract

Pathological inclusions containing transactive response DNA-binding protein 43 kDa (TDP-43) are common in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). TDP-43 normally localizes predominantly to the nucleus, but during disease progression, it mislocalizes to the cytoplasm. We expressed TDP-43 in rats by an adeno-associated virus (AAV9) gene transfer method that transduces neurons throughout the central nervous system (CNS). To mimic the aberrant cytoplasmic TDP-43 found in disease, we expressed a form of TDP-43 with mutations in the nuclear localization signal sequence (TDP-NLS). The TDP-NLS was detected in both the cytoplasm and the nucleus of transduced neurons. Unlike wild-type TDP-43, expression of TDP-NLS did not induce mortality. However, the TDP-NLS induced disease-relevant motor impairments over 24 weeks. We compared the TDP-NLS to a 25 kDa C-terminal proaggregatory fragment of TDP-43 (TDP-25). The clinical phenotype of forelimb impairment was pronounced with the TDP-25 form, supporting a role of this C-terminal fragment in pathogenesis. The results advance previous rodent models by inducing cytoplasmic expression of TDP-43 in the spinal cord, and the non-lethal phenotype enabled long-term study. Approaching a more relevant disease state in an animal model that more closely mimics underlying mechanisms in human disease could unlock our ability to develop therapeutics.

Original languageEnglish
Pages (from-to)1324-1334
Number of pages11
JournalMolecular Therapy
Volume21
Issue number7
DOIs
StatePublished - 1 Jan 2013

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Forelimb
Amyotrophic Lateral Sclerosis
Cytoplasm
Phenotype
Neurons
Nuclear Localization Signals
Dependovirus
DNA-Binding Proteins
Protein Sorting Signals
Neurodegenerative Diseases
Disease Progression
Rodentia
Spinal Cord
Central Nervous System
Animal Models
Mutation
Mortality
Genes
Therapeutics

Cite this

Dayton, R. D., Gitcho, M. A., Orchard, E. A., Wilson, J. D., Wang, D. B., Cain, C. D., ... Klein, R. L. (2013). Selective forelimb impairment in rats expressing a pathological TDP-43 25 kDa C-terminal fragment to mimic amyotrophic lateral sclerosis. Molecular Therapy, 21(7), 1324-1334. https://doi.org/10.1038/mt.2013.88
Dayton, Robert D. ; Gitcho, Michael A. ; Orchard, Elysse A. ; Wilson, Jon D. ; Wang, David B. ; Cain, Cooper D. ; Johnson, Jeffrey A. ; Zhang, Yong Jie ; Petrucelli, Leonard ; Mathis, James Michael ; Klein, Ronald L. / Selective forelimb impairment in rats expressing a pathological TDP-43 25 kDa C-terminal fragment to mimic amyotrophic lateral sclerosis. In: Molecular Therapy. 2013 ; Vol. 21, No. 7. pp. 1324-1334.
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abstract = "Pathological inclusions containing transactive response DNA-binding protein 43 kDa (TDP-43) are common in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). TDP-43 normally localizes predominantly to the nucleus, but during disease progression, it mislocalizes to the cytoplasm. We expressed TDP-43 in rats by an adeno-associated virus (AAV9) gene transfer method that transduces neurons throughout the central nervous system (CNS). To mimic the aberrant cytoplasmic TDP-43 found in disease, we expressed a form of TDP-43 with mutations in the nuclear localization signal sequence (TDP-NLS). The TDP-NLS was detected in both the cytoplasm and the nucleus of transduced neurons. Unlike wild-type TDP-43, expression of TDP-NLS did not induce mortality. However, the TDP-NLS induced disease-relevant motor impairments over 24 weeks. We compared the TDP-NLS to a 25 kDa C-terminal proaggregatory fragment of TDP-43 (TDP-25). The clinical phenotype of forelimb impairment was pronounced with the TDP-25 form, supporting a role of this C-terminal fragment in pathogenesis. The results advance previous rodent models by inducing cytoplasmic expression of TDP-43 in the spinal cord, and the non-lethal phenotype enabled long-term study. Approaching a more relevant disease state in an animal model that more closely mimics underlying mechanisms in human disease could unlock our ability to develop therapeutics.",
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Dayton, RD, Gitcho, MA, Orchard, EA, Wilson, JD, Wang, DB, Cain, CD, Johnson, JA, Zhang, YJ, Petrucelli, L, Mathis, JM & Klein, RL 2013, 'Selective forelimb impairment in rats expressing a pathological TDP-43 25 kDa C-terminal fragment to mimic amyotrophic lateral sclerosis', Molecular Therapy, vol. 21, no. 7, pp. 1324-1334. https://doi.org/10.1038/mt.2013.88

Selective forelimb impairment in rats expressing a pathological TDP-43 25 kDa C-terminal fragment to mimic amyotrophic lateral sclerosis. / Dayton, Robert D.; Gitcho, Michael A.; Orchard, Elysse A.; Wilson, Jon D.; Wang, David B.; Cain, Cooper D.; Johnson, Jeffrey A.; Zhang, Yong Jie; Petrucelli, Leonard; Mathis, James Michael; Klein, Ronald L.

In: Molecular Therapy, Vol. 21, No. 7, 01.01.2013, p. 1324-1334.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Selective forelimb impairment in rats expressing a pathological TDP-43 25 kDa C-terminal fragment to mimic amyotrophic lateral sclerosis

AU - Dayton, Robert D.

AU - Gitcho, Michael A.

AU - Orchard, Elysse A.

AU - Wilson, Jon D.

AU - Wang, David B.

AU - Cain, Cooper D.

AU - Johnson, Jeffrey A.

AU - Zhang, Yong Jie

AU - Petrucelli, Leonard

AU - Mathis, James Michael

AU - Klein, Ronald L.

PY - 2013/1/1

Y1 - 2013/1/1

N2 - Pathological inclusions containing transactive response DNA-binding protein 43 kDa (TDP-43) are common in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). TDP-43 normally localizes predominantly to the nucleus, but during disease progression, it mislocalizes to the cytoplasm. We expressed TDP-43 in rats by an adeno-associated virus (AAV9) gene transfer method that transduces neurons throughout the central nervous system (CNS). To mimic the aberrant cytoplasmic TDP-43 found in disease, we expressed a form of TDP-43 with mutations in the nuclear localization signal sequence (TDP-NLS). The TDP-NLS was detected in both the cytoplasm and the nucleus of transduced neurons. Unlike wild-type TDP-43, expression of TDP-NLS did not induce mortality. However, the TDP-NLS induced disease-relevant motor impairments over 24 weeks. We compared the TDP-NLS to a 25 kDa C-terminal proaggregatory fragment of TDP-43 (TDP-25). The clinical phenotype of forelimb impairment was pronounced with the TDP-25 form, supporting a role of this C-terminal fragment in pathogenesis. The results advance previous rodent models by inducing cytoplasmic expression of TDP-43 in the spinal cord, and the non-lethal phenotype enabled long-term study. Approaching a more relevant disease state in an animal model that more closely mimics underlying mechanisms in human disease could unlock our ability to develop therapeutics.

AB - Pathological inclusions containing transactive response DNA-binding protein 43 kDa (TDP-43) are common in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). TDP-43 normally localizes predominantly to the nucleus, but during disease progression, it mislocalizes to the cytoplasm. We expressed TDP-43 in rats by an adeno-associated virus (AAV9) gene transfer method that transduces neurons throughout the central nervous system (CNS). To mimic the aberrant cytoplasmic TDP-43 found in disease, we expressed a form of TDP-43 with mutations in the nuclear localization signal sequence (TDP-NLS). The TDP-NLS was detected in both the cytoplasm and the nucleus of transduced neurons. Unlike wild-type TDP-43, expression of TDP-NLS did not induce mortality. However, the TDP-NLS induced disease-relevant motor impairments over 24 weeks. We compared the TDP-NLS to a 25 kDa C-terminal proaggregatory fragment of TDP-43 (TDP-25). The clinical phenotype of forelimb impairment was pronounced with the TDP-25 form, supporting a role of this C-terminal fragment in pathogenesis. The results advance previous rodent models by inducing cytoplasmic expression of TDP-43 in the spinal cord, and the non-lethal phenotype enabled long-term study. Approaching a more relevant disease state in an animal model that more closely mimics underlying mechanisms in human disease could unlock our ability to develop therapeutics.

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