AAV transduction of dopamine neurons with constitutively active rheb protects from neurodegeneration and mediates axon regrowth
Open accessAbstract
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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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.”
From BDNF as a Promising Therapeutic Agent in Parkinson’s Disease (2020) · cites this paper as [92]
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].”
From BDNF as a Promising Therapeutic Agent in Parkinson’s Disease (2020) · cites this paper as [92]
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].”
From BDNF as a Promising Therapeutic Agent in Parkinson’s Disease (2020) · cites this paper as [92]
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Naringin: A Protector of the Nigrostriatal Dopaminergic Projection
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Self-citationPerspectives of RAS and RHEB GTPase Signaling Pathways in Regenerating Brain Neurons
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Self-citationDysregulation of Human Somatic piRNA Expression in Parkinson’s Disease Subtypes and Stages
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Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2
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Self-citationStriatal Reinnervation Process after Acute Methamphetamine-Induced Dopaminergic Degeneration in Mice
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Self-citationUpregulation of neuronal astrocyte elevated gene-1 protects nigral dopaminergic neurons in vivo
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Self-citationProthrombin Kringle-2: a potential inflammatory pathogen in the parkinsonian dopaminergic system
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Self-citationInduction of GDNF and GFRα-1 Following AAV1-Rheb(S16H) Administration in the Hippocampus in vivo
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Self-citationRheb in neuronal degeneration, regeneration, and connectivity
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Therapeutic Potential of AAV1-Rheb(S16H) Transduction Against Alzheimer’s Disease
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Self-citationTherapeutic Potential of AAV1-Rheb(S16H) Transduction against Neurodegenerative Diseases
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Self-citationRoles of Rheb(S16H) in substantia nigra pars compacta dopaminergic neurons in vivo
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Self-citationExpression mediated by three partial sequences of the human tyrosine hydroxylase promoter in vivo
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Self-citationIntracerebellar upregulation of Rheb(S16H) ameliorates motor dysfunction in mice with SCA2
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Structure and Function of the mTOR Activator Rheb
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Self-citationIn memoriam: Robert E. Burke, MD, 1949–2018
Fahn, S., Sulzer, D. L., Kang, U. J., & Bressman, S. (2019) · Movement Disorders · doi:10.1002/mds.27612
- 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)
- PMC
- PMC3277224
- 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
- hybrid
- doi.org
- Licence
- 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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