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@ARTICLE{Pa:1031535,
author = {Paß, Thomas and Ricke, Konrad M and Hofmann, Pierre and
Chowdhury, Roy S and Nie, Yu and Chinnery, Patrick and
Endepols, Heike and Neumaier, Bernd and Carvalho, André and
Rigoux, Lionel and Steculorum, Sophie M and Prudent, Julien
and Riemer, Trine and Aswendt, Markus and Liss, Birgit and
Brachvogel, Bent and Wiesner, Rudolf J},
title = {{P}reserved striatal innervation maintains motor function
despite severe loss of nigral dopaminergic neurons},
journal = {Brain},
volume = {147},
number = {9},
issn = {0006-8950},
address = {Oxford},
publisher = {Oxford Univ. Press},
reportid = {FZJ-2024-05730},
pages = {3189 - 3203},
year = {2024},
note = {T.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.},
abstract = {Degeneration 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.},
cin = {INM-5},
ddc = {610},
cid = {I:(DE-Juel1)INM-5-20090406},
pnm = {5253 - Neuroimaging (POF4-525)},
pid = {G:(DE-HGF)POF4-5253},
typ = {PUB:(DE-HGF)16},
pubmed = {38574200},
UT = {WOS:001296119400001},
doi = {10.1093/brain/awae089},
url = {https://juser.fz-juelich.de/record/1031535},
}