Journal Article

FZJ-2024-05730

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Preserved striatal innervation maintains motor function despite severe loss of nigral dopaminergic neurons

Paß, T. (Corresponding author) ; Ricke, K. M. ; Hofmann, P. ; Chowdhury, R. S. ; Nie, Y. ; Chinnery, P. ; Endepols, H.FZJ* ; Neumaier, B.FZJ* ; Carvalho, A. ; Rigoux, L. ; Steculorum, S. M. ; Prudent, J. ; Riemer, T. ; Aswendt, M. ; Liss, B. ; Brachvogel, B. ; Wiesner, R. J.

2024
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/brain/awae089

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.

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.

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Contributing Institute(s):

1. Nuklearchemie (INM-5)

Research Program(s):

1. 5253 - Neuroimaging (POF4-525) (POF4-525)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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