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001031535 1001_ $$0P:(DE-HGF)0$$aPaß, Thomas$$b0$$eCorresponding author
001031535 245__ $$aPreserved striatal innervation maintains motor function despite severe loss of nigral dopaminergic neurons
001031535 260__ $$aOxford$$bOxford Univ. Press$$c2024
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001031535 500__ $$aT.P and R.J.W received funds from the Center of Molecular Medicine Cologne (CMMC, C17); K.M.R. received funding from Parkinson Canada Basic Research Fellowship (BRF-2021-0000000048); A.C. received support by the Cologne Graduate School of Ageing Research; R.S.C. and J.P. received funds from the Medical Research Council UK (MC_UU_00028/5). Y.N. and P.C. were supported by a Wellcome Collaborative Award (224486/Z/21/Z), the Medical Research Council Mitochondrial Biology Unit (MC_UU_00028/7), the Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease (MR/S005021/1), the Leverhulme Trust (RPG-2018-408), an MRC research grant (MR/S035699/1), an Alzheimer’s Society Project Grant (AS-PG-18b-022), and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014); M.A. acknowledges financial support by the Friebe Foundation (T0498/28960/16) and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Project-ID 431549029—SFB 1451.
001031535 520__ $$aDegeneration of dopaminergic neurons in the substantia nigra and their striatal axon terminals causes cardinal motorsymptoms of Parkinson’s disease. In idiopathic cases, high levels of mitochondrial DNA alterations, leading tomitochondrial 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 dopaminergicneurons, leading to accelerated mitochondrial DNA mutations. These K320E-TwinkleDaN mice showed normal motorfunction at 20 months of age, although ∼70% of nigral dopaminergic neurons had perished. Remaining neurons stillpreserved ∼75% of axon terminals in the dorsal striatum and enabled normal dopamine release. Transcriptome analysisand 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 ofmitochondrial DNA mutations and maintain motor control.
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001031535 7001_ $$0P:(DE-HGF)0$$aRicke, Konrad M$$b1
001031535 7001_ $$0P:(DE-HGF)0$$aHofmann, Pierre$$b2
001031535 7001_ $$0P:(DE-HGF)0$$aChowdhury, Roy S$$b3
001031535 7001_ $$0P:(DE-HGF)0$$aNie, Yu$$b4
001031535 7001_ $$0P:(DE-HGF)0$$aChinnery, Patrick$$b5
001031535 7001_ $$0P:(DE-Juel1)180330$$aEndepols, Heike$$b6
001031535 7001_ $$0P:(DE-Juel1)166419$$aNeumaier, Bernd$$b7
001031535 7001_ $$0P:(DE-HGF)0$$aCarvalho, André$$b8
001031535 7001_ $$0P:(DE-HGF)0$$aRigoux, Lionel$$b9
001031535 7001_ $$0P:(DE-HGF)0$$aSteculorum, Sophie M$$b10
001031535 7001_ $$0P:(DE-HGF)0$$aPrudent, Julien$$b11
001031535 7001_ $$0P:(DE-HGF)0$$aRiemer, Trine$$b12
001031535 7001_ $$0P:(DE-Juel1)196051$$aAswendt, Markus$$b13
001031535 7001_ $$0P:(DE-HGF)0$$aLiss, Birgit$$b14
001031535 7001_ $$0P:(DE-HGF)0$$aBrachvogel, Bent$$b15
001031535 7001_ $$0P:(DE-HGF)0$$aWiesner, Rudolf J$$b16
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