Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant α-synuclein rat model of parkinsonism
Parkinson's disease (PD) is a neurodegenerative movement disorder, which affects approximately 1–2% of the population over 60 years of age. Current treatments for PD are symptomatic, and the pathology of the disease continues to progresses over time until palliative care is required. Mitochondr...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-10-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996117301365 |
| _version_ | 1823927002380369920 |
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| author | Jacqueline A. Gleave Lindsay R. Arathoon Dennison Trinh Kristin E. Lizal Nicolas Giguère James H.M. Barber Zainab Najarali M. Hassan Khan Sherri L. Thiele Mahin S. Semmen James B. Koprich Jonathan M. Brotchie James H. Eubanks Louis-Eric Trudeau Joanne E. Nash |
| author_facet | Jacqueline A. Gleave Lindsay R. Arathoon Dennison Trinh Kristin E. Lizal Nicolas Giguère James H.M. Barber Zainab Najarali M. Hassan Khan Sherri L. Thiele Mahin S. Semmen James B. Koprich Jonathan M. Brotchie James H. Eubanks Louis-Eric Trudeau Joanne E. Nash |
| author_sort | Jacqueline A. Gleave |
| collection | DOAJ |
| description | Parkinson's disease (PD) is a neurodegenerative movement disorder, which affects approximately 1–2% of the population over 60 years of age. Current treatments for PD are symptomatic, and the pathology of the disease continues to progresses over time until palliative care is required. Mitochondria are key players in the pathology of PD. Genetic and post mortem studies have shown a large number of mitochondrial abnormalities in the substantia nigra pars compacta (SNc) of the parkinsonian brain. Furthermore, physiologically, mitochondria of nigral neurons are constantly under unusually high levels of metabolic stress because of the excitatory properties and architecture of these neurons. The protein deacetylase, Sirtuin 3 (SIRT3) reduces the impact subcellular stresses on mitochondria, by stabilising the electron transport chain (ETC), and reducing oxidative stress. We hypothesised that viral overexpression of myc-tagged SIRT3 (SIRT3-myc) would slow the progression of PD pathology, by enhancing the functional capacity of mitochondria. For this study, SIRT3-myc was administered both before and after viral induction of parkinsonism with the AAV-expressing mutant (A53T) α-synuclein. SIRT3-myc corrected behavioural abnormalities, as well as changes in striatal dopamine turnover. SIRT3-myc also prevented degeneration of dopaminergic neurons in the SNc. These effects were apparent, even when SIRT3-myc was transduced after the induction of parkinsonism, at a time point when cell stress and behavioural abnormalities are already observed. Furthermore, in an isolated mitochondria nigral homogenate prepared from parkinsonian SIRT3–myc infected animals, SIRT3 targeted the mitochondria, to reduce protein acetylation levels. Our results demonstrate that transduction of SIRT3 has the potential to be an effective disease-modifying strategy for patients with PD. This study also provides potential mechanisms for the protective effects of SIRT3-myc. |
| first_indexed | 2024-12-16T20:32:44Z |
| format | Article |
| id | doaj.art-62237862f4484511b63bc2058c5fb394 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-16T20:32:44Z |
| publishDate | 2017-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-62237862f4484511b63bc2058c5fb3942022-12-21T22:17:23ZengElsevierNeurobiology of Disease1095-953X2017-10-01106133146Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant α-synuclein rat model of parkinsonismJacqueline A. Gleave0Lindsay R. Arathoon1Dennison Trinh2Kristin E. Lizal3Nicolas Giguère4James H.M. Barber5Zainab Najarali6M. Hassan Khan7Sherri L. Thiele8Mahin S. Semmen9James B. Koprich10Jonathan M. Brotchie11James H. Eubanks12Louis-Eric Trudeau13Joanne E. Nash14Centre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, CanadaCentre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, CanadaCentre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, CanadaCentre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, CanadaDepartment of Pharmacology, Central Nervous System Research Group (GRSNC), Faculty of Medicine, Universite de Montreal, Montreal, Quebec, Canada; Department Neuroscience, Central Nervous System Research Group (GRSNC), Faculty of Medicine, Universite de Montreal, Montreal, Quebec, CanadaCentre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, CanadaCentre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, CanadaCentre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, CanadaCentre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, CanadaCentre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, CanadaKrembil Research Institute, Toronto Western Hospital, Toronto, Ontario, CanadaKrembil Research Institute, Toronto Western Hospital, Toronto, Ontario, CanadaKrembil Research Institute, Toronto Western Hospital, Toronto, Ontario, CanadaDepartment of Pharmacology, Central Nervous System Research Group (GRSNC), Faculty of Medicine, Universite de Montreal, Montreal, Quebec, Canada; Department Neuroscience, Central Nervous System Research Group (GRSNC), Faculty of Medicine, Universite de Montreal, Montreal, Quebec, CanadaCentre for the Neurobiology of Stress, Department of Biological Sciences, University of Toronto Scarborough, Toronto, Ontario, Canada; Corresponding author.Parkinson's disease (PD) is a neurodegenerative movement disorder, which affects approximately 1–2% of the population over 60 years of age. Current treatments for PD are symptomatic, and the pathology of the disease continues to progresses over time until palliative care is required. Mitochondria are key players in the pathology of PD. Genetic and post mortem studies have shown a large number of mitochondrial abnormalities in the substantia nigra pars compacta (SNc) of the parkinsonian brain. Furthermore, physiologically, mitochondria of nigral neurons are constantly under unusually high levels of metabolic stress because of the excitatory properties and architecture of these neurons. The protein deacetylase, Sirtuin 3 (SIRT3) reduces the impact subcellular stresses on mitochondria, by stabilising the electron transport chain (ETC), and reducing oxidative stress. We hypothesised that viral overexpression of myc-tagged SIRT3 (SIRT3-myc) would slow the progression of PD pathology, by enhancing the functional capacity of mitochondria. For this study, SIRT3-myc was administered both before and after viral induction of parkinsonism with the AAV-expressing mutant (A53T) α-synuclein. SIRT3-myc corrected behavioural abnormalities, as well as changes in striatal dopamine turnover. SIRT3-myc also prevented degeneration of dopaminergic neurons in the SNc. These effects were apparent, even when SIRT3-myc was transduced after the induction of parkinsonism, at a time point when cell stress and behavioural abnormalities are already observed. Furthermore, in an isolated mitochondria nigral homogenate prepared from parkinsonian SIRT3–myc infected animals, SIRT3 targeted the mitochondria, to reduce protein acetylation levels. Our results demonstrate that transduction of SIRT3 has the potential to be an effective disease-modifying strategy for patients with PD. This study also provides potential mechanisms for the protective effects of SIRT3-myc.http://www.sciencedirect.com/science/article/pii/S0969996117301365Parkinson's diseaseVirally over-expressing mutant α-synuclein ratNeuroprotectionSubstantia nigraMitochondriaSirtuin 3 |
| spellingShingle | Jacqueline A. Gleave Lindsay R. Arathoon Dennison Trinh Kristin E. Lizal Nicolas Giguère James H.M. Barber Zainab Najarali M. Hassan Khan Sherri L. Thiele Mahin S. Semmen James B. Koprich Jonathan M. Brotchie James H. Eubanks Louis-Eric Trudeau Joanne E. Nash Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant α-synuclein rat model of parkinsonism Neurobiology of Disease Parkinson's disease Virally over-expressing mutant α-synuclein rat Neuroprotection Substantia nigra Mitochondria Sirtuin 3 |
| title | Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant α-synuclein rat model of parkinsonism |
| title_full | Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant α-synuclein rat model of parkinsonism |
| title_fullStr | Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant α-synuclein rat model of parkinsonism |
| title_full_unstemmed | Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant α-synuclein rat model of parkinsonism |
| title_short | Sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally-expressing mutant α-synuclein rat model of parkinsonism |
| title_sort | sirtuin 3 rescues neurons through the stabilisation of mitochondrial biogenetics in the virally expressing mutant α synuclein rat model of parkinsonism |
| topic | Parkinson's disease Virally over-expressing mutant α-synuclein rat Neuroprotection Substantia nigra Mitochondria Sirtuin 3 |
| url | http://www.sciencedirect.com/science/article/pii/S0969996117301365 |
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