Cited by 107Virus-based gene therapy researchParkinson's Disease Mechanisms and TreatmentsNerve injury and regeneration

AAV transduction of dopamine neurons with constitutively active rheb protects from neurodegeneration and mediates axon regrowth

Open access
Kim, Sang Ryong, Kareva, Tatyana, Yarygina, Olga, Kholodilov, Nikolai, Burke, Robert E·2012·Molecular Therapy

Abstract

There are currently no therapies that provide either protection or restoration of neuronal function for adult-onset neurodegenerative diseases such as Parkinson's disease (PD). Many clinical efforts to provide such benefits by infusion of neurotrophic factors have failed, in spite of robust effects in preclinical assessments. One important reason for these failures is the difficulty, due to diffusion limits, of providing these protein molecules in sufficient amounts to the intended cellular targets in the central nervous system. This challenge suggests an alternative approach, that of viral vector transduction to directly activate the intracellular signaling pathways that mediate neurotrophic effects. To this end we have investigated the ability of a constitutively active form of the GTPase Rheb, an important activator of mammalian target of rapamycin (mTor) signaling, to mediate neurotrophic effects in dopamine neurons of the substantia nigra (SN), a population of neurons affected in PD. We find that constitutively active hRheb(S16H) induces many neurotrophic effects in mice, including abilities to both preserve and restore the nigrostriatal dopaminergic axonal projections in a highly destructive neurotoxin model. We conclude that direct viral vector transduction of vulnerable neuronal populations to activate intracellular neurotrophic signaling pathways offers promise for the treatment of neurodegenerative disease.

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Crossref · 10.1038/mt.2011.213

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  • In animal models of Parkinson's disease, BDNF enhances the survival of dopaminergic neurons.

    “In animal models of Parkinson’s disease (PD), BDNF enhances the survival of dopaminergic neurons, improves dopaminergic neurotransmission and motor performance.”
  • When induction of parkinsonism by 6-OHDA lesion was followed by BDNF treatment, there seemed to be no recovery of the dopaminergic neuron number in substantia nigra.

    “Similarly controversial results were obtained when induction of parkinsonism by 6-OHDA lesion was followed by BDNF treatment. There seemed to be no recovery of the dopaminergic neurons number in SN [92,95,97,98].”
  • In the vast majority of studies with BDNF administration before induction of parkinsonism, the results revealed at least partial prevention of neuronal cell loss.

    “In the vast majority of studies with BDNF administration before induction of parkinsonism, the research results revealed at least partial prevention of neuronal cell loss [89,90,92,93,99,101].”

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Authors
Kim, S. R., Kareva, T., Yarygina, O., Kholodilov, N., & Burke, R. E.
Affiliations
Columbia University (US)
Corresponding author
Burke, Robert E
Venue
Molecular Therapy
Publisher
Elsevier BV
Published
2012-02
Volume
20
Issue
2
Pages
275-286
ISSN
1525-0016 (ISSN-L)
OpenAlex
W2059374893
Cited by
107
References
51
Citations by year
2026: 3 · 2025: 4 · 2024: 4 · 2023: 7 · 2022: 4 · 2021: 6 · 2020: 11 · 2019: 8 · 2018: 8 · 2017: 9 · 2016: 8 · 2015: 10 · 2014: 13 · 2013: 7 · 2012: 4
FWCI
4.99
Type
journal article
Language
en
Open access
Locations
  • Molecular Therapy (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (NS26836, P50NS038370, R56NS026836, NS38370, R01NS026836)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
Keywords
Parkinson's disease, dopaminergic neurons, substantia nigra, Rheb, mTOR signaling, viral transduction, AAV, neuroprotection, axon regeneration, nigrostriatal pathway, neurodegeneration, neurotrophic signaling
MeSH terms
Ras Homolog Enriched in Brain Protein, Dependovirus, Animals, Axons, Carrier Proteins, Corpus Striatum, Disease Models, Animal, Genetic Vectors, Humans, Male, Mice, Inbred C57BL, Neuropeptides, Parkinson Disease, Phosphoproteins, Phosphorylation, Substantia Nigra, Transduction, Genetic, Genetic Therapy, Signal Transduction, Oxidopamine, Cell Cycle Proteins, Monomeric GTP-Binding Proteins, Eukaryotic Initiation Factors, Adaptor Proteins, Signal Transducing, Mice, Dopaminergic Neurons

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