Preserved striatal innervation maintains motor function despite severe loss of nigral dopaminergic neurons.

Autor:	Paß T; Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany., Ricke KM; Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany., Hofmann P; Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany., Chowdhury RS; MRC Mitochondrial Biology Unit, University of Cambridge, CB2 0XY Cambridge, UK., Nie Y; MRC Mitochondrial Biology Unit, University of Cambridge, CB2 0XY Cambridge, UK., Chinnery P; MRC Mitochondrial Biology Unit, University of Cambridge, CB2 0XY Cambridge, UK., Endepols H; Faculty of Medicine and University Hospital Cologne, University of Cologne, Institute of Radiochemistry and Experimental Molecular Imaging, 50937 Cologne, Germany.; Department of Nuclear Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50937 Cologne, Germany., Neumaier B; Faculty of Medicine and University Hospital Cologne, University of Cologne, Institute of Radiochemistry and Experimental Molecular Imaging, 50937 Cologne, Germany.; Forschungszentrum Jülich GmbH, Institute of Neuroscience and Medicine, Nuclear Chemistry (INM-5), 52425 Jülich, Germany.; Max Planck Institute for Metabolism Research, 50931 Cologne, Germany., Carvalho A; Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany., Rigoux L; Max Planck Institute for Metabolism Research, 50931 Cologne, Germany., Steculorum SM; Max Planck Institute for Metabolism Research, 50931 Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany., Prudent J; MRC Mitochondrial Biology Unit, University of Cambridge, CB2 0XY Cambridge, UK., Riemer T; Department of Paediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine, University of Cologne, 50937 Cologne, Germany., Aswendt M; Department of Neurology, University of Cologne, Faculty of Medicine and University Hospital Cologne, 50937 Cologne, Germany., Liss B; Institute of Applied Physiology, University of Ulm, 89081 Ulm, Germany., Brachvogel B; Department of Paediatrics and Adolescent Medicine, Experimental Neonatology, Faculty of Medicine, University of Cologne, 50937 Cologne, Germany., Wiesner RJ; Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Faculty of Medicine and University Hospital Cologne, 50931 Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD) and Centre for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2024 Sep 03; Vol. 147 (9), pp. 3189-3203.
DOI:	10.1093/brain/awae089
Abstrakt:	Degeneration of dopaminergic neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinson's disease. In idiopathic cases, high levels of mitochondrial DNA alterations, leading to mitochondrial dysfunction, are a central feature of these vulnerable neurons. Here we present a mouse model expressing the K320E variant of the mitochondrial helicase Twinkle in dopaminergic neurons, leading to accelerated mitochondrial DNA mutations. These K320E-TwinkleDaN mice showed normal motor function at 20 months of age, although ∼70% of nigral dopaminergic neurons had perished. Remaining neurons still preserved ∼75% of axon terminals in the dorsal striatum and enabled normal dopamine release. Transcriptome analysis and viral tracing confirmed compensatory axonal sprouting of the surviving neurons. We conclude that a small population of substantia nigra dopaminergic neurons is able to adapt to the accumulation of mitochondrial DNA mutations and maintain motor control. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
Databáze:	MEDLINE
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