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Disruption of mitochondrial complex I induces progressive parkinsonism.

ABSTRACT: Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease¹. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear². Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm^3,4.

SUBMITTER: Gonzalez-Rodriguez P

PROVIDER: S-EPMC9189968 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Disruption of mitochondrial complex I induces progressive parkinsonism.

González-Rodríguez Patricia P Zampese Enrico E Stout Kristen A KA Guzman Jaime N JN Ilijic Ema E Yang Ben B Tkatch Tatiana T Stavarache Mihaela A MA Wokosin David L DL Gao Lin L Kaplitt Michael G MG López-Barneo José J Schumacker Paul T PT Surmeier D James DJ

Nature 20211103 7886

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease<sup>1</sup>. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear<sup>2</sup>. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenoty ...[more]

PMID: 34732887

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Project description:BackgroundDifferentiating progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) is clinically challenging.ObjectiveThis study aimed to develop an automated Magnetic Resonance Parkinsonism Index 2.0 (MRPI 2.0) algorithm to distinguish PSP-P from PD and to validate its diagnostic performance in two large independent cohorts.MethodsWe enrolled 676 participants: a training cohort (n = 346; 43 PSP-P, 194 PD, and 109 control subjects) from our center and an independent testing cohort (n = 330; 62 PSP-P, 171 PD, and 97 control subjects) from an international research group. We developed a new in-house algorithm for MRPI 2.0 calculation and assessed its performance in distinguishing PSP-P from PD and control subjects in both cohorts using receiver operating characteristic curves.ResultsThe automated MRPI 2.0 showed excellent performance in differentiating patients with PSP-P from patients with PD and control subjects both in the training cohort (area under the receiver operating characteristic curve [AUC] = 0.93 [95% confidence interval, 0.89-0.98] and AUC = 0.97 [0.93-1.00], respectively) and in the international testing cohort (PSP-P versus PD, AUC = 0.92 [0.87-0.97]; PSP-P versus controls, AUC = 0.94 [0.90-0.98]), suggesting the generalizability of the results. The automated MRPI 2.0 also accurately distinguished between PSP-P and PD in the early stage of the diseases (AUC = 0.91 [0.84-0.97]). A strong correlation (r = 0.91, P < 0.001) was found between automated and manual MRPI 2.0 values.ConclusionsOur study provides an automated, validated, and generalizable magnetic resonance biomarker to distinguish PSP-P from PD. The use of the automated MRPI 2.0 algorithm rather than manual measurements could be important to standardize measures in patients with PSP-P across centers, with a positive impact on multicenter studies and clinical trials involving patients from different geographic regions. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Disruption of mitochondrial complex I induces progressive parkinsonism.

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Disruption of mitochondrial complex I induces progressive parkinsonism.

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