Relationship between brain iron deposition and mitochondrial dysfunction in idiopathic Parkinson’s disease

Prasuhn, Jannik; Göttlich, Martin; Gerkan, Friederike; Kourou, Sofia; Ebeling, Britt; Kasten, Meike; Hanßen, Henrike; Klein, Christine; Brüggemann, Norbert

doi:10.1186/s10020-021-00426-9

Cited by 18 publications

(15 citation statements)

References 47 publications

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“…The abnormal iron deposition is implicated in age-related neurodegenerative disorders, including Alzheimer’s disease 14 and Parkinson’s disease, 15 and patients undergoing HD. 5 , 16 Abnormal iron metabolism and tissue iron overload can be found in the brains of patients undergoing HD, 17 suggesting the role of iron metabolism dysfunction in cognitive impairment development.…”

Section: Introductionmentioning

confidence: 99%

Association between susceptibility value and cerebral blood flow in the bilateral putamen in patients undergoing hemodialysis

Wang

Song

et al. 2022

J Cereb Blood Flow Metab

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Hemodialysis (HD) is the most regularly applied replacement therapy for end-stage renal disease, but it may result in brain injuries. The correlation between cerebral blood flow (CBF) alteration and iron deposition has not been investigated in patients undergoing HD. Ferritin level may be a dominant factor in CBF and iron deposition change. We hypothesize that ferritin level might be the key mediator between iron deposition and CBF alteration. The correlation in the putamen was estimated between the susceptibility values and CBF in patients undergoing HD. Compared with healthy controls, patients showed more altered global susceptibility values and CBF. The susceptibility value was negatively correlated with CBF in the putamen in patients. Moreover, the susceptibility value was negatively correlated with ferritin level and positively correlated with serum iron level in the putamen of patients. CBF was positively correlated with ferritin level and negatively correlated with serum iron level in the putamen of patients. These findings indicate that iron dyshomeostasis and vascular damage might exist in the putamen in patients. The results revealed that iron dyshomeostasis and vascular damage in the putamen may be potential neural mechanisms for neurodegenerative processes in patients undergoing HD.

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Section: Introductionmentioning

confidence: 99%

Association between susceptibility value and cerebral blood flow in the bilateral putamen in patients undergoing hemodialysis

Wang

Song

et al. 2022

J Cereb Blood Flow Metab

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“…None of the above-reported HEP levels showed any significant association with our volumetric data or observed LEDD levels, which aligns well with our previous reports. 9,14,16 In addition, no visit effects were observed for any clinical-or neuroimagingrelated data (in covariate testing).…”

Section: Resultsmentioning

confidence: 94%

Levodopa Impairs the Energy Metabolism of the Basal Ganglia In Vivo

Prasuhn,

Schiefen,

Güber

et al. 2024

Annals of Neurology

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ObjectiveOne proposed mechanism of disease progression in Parkinson's disease includes the interplay of endogenous dopamine toxicity and mitochondrial dysfunction. However, the in‐vivo effects of exogenous dopamine administration on cerebral bioenergetics are unknown.MethodsWe performed a double‐blinded, cross‐over, placebo‐controlled trial. Participants received either 200/50 mg levodopa/benserazide or a placebo and vice versa on the second study visit. Clinical assessments and multimodal neuroimaging were performed, including 31phosphorus magnetic resonance spectroscopy of the basal ganglia and the midbrain.ResultsIn total, 20 (6 female) patients with Parkinson's disease and 22 sex‐ and age‐matched healthy controls (10 female) were enrolled. Treatment with levodopa/benserazide but not with placebo resulted in a substantial reduction of high‐energy phosphorus‐containing metabolites in the basal ganglia (patients with Parkinson's disease: −40%; healthy controls: −39%) but not in the midbrain. There were no differences in high‐energy phosphorus‐containing metabolites for patients with Parkinson's disease compared to healthy controls in the OFF state and treatment response.InterpretationExogenously administered levodopa/benserazide strongly interferes with basal ganglia high‐energy phosphorus‐containing metabolite levels in both groups. The lack of effects on midbrain levels suggests that the observed changes are limited to the site of dopamine action. ANN NEUROL 2024

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“…Deficits of complex-I of the mitochondrial respiratory chain is a signature pathology in PD [49]. Impairment of mitochondrial function is characterized by generation of reactive oxygen species, cytochrome-c release, ATP depletion, and caspase-3 activation [50,51].…”

Section: Mitochondrial Dysfunction and Oxidative Stressmentioning

confidence: 99%

A Mouse Model to Test Novel Therapeutics for Parkinson's Disease: an Update on the Thy1-aSyn (“line 61”) Mice

et al. 2023

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Development of neuroprotective therapeutics for Parkinson’s disease (PD) is facing a lack of translation from pre-clinical to clinical trials. One strategy for improvement is to increase predictive validity of pre-clinical studies by using extensively characterized animal models with a comprehensive set of validated pharmacodynamic readouts. Mice over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter (Thy1-aSyn line 61) reproduce key features of sporadic PD, such as progressive loss of striatal dopamine, alpha-synuclein pathology, deficits in motor and non-motor functions, and elevation of inflammatory markers. Extensive work with this model by multiple laboratories over the past decade further increased confidence in its robustness and validity, especially for analyzing pathomechanisms of alpha-synuclein pathology and down-stream pathways, and for pre-clinical drug testing. Interestingly, while postnatal transgene expression is widespread in central and peripheral neurons, the extent and progression of down-stream pathology differs between brain regions, thereby replicating the characteristic selective vulnerability of neurodegenerative diseases. In-depth characterization of these readouts in conjunction with behavioral deficits has led to more informative endpoints for pre-clinical trials. Each drug tested in Thy1-aSyn line 61 enhances knowledge on how molecular targets, pathology, and functional behavioral readouts are interconnected, thereby further optimizing the platform towards predictive validity for clinical trials. Here, we present the current state of the art using Thy1-aSyn line 61 for drug target discovery, validation, and pre-clinical testing.

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Relationship between brain iron deposition and mitochondrial dysfunction in idiopathic Parkinson’s disease

Cited by 18 publications

References 47 publications

Association between susceptibility value and cerebral blood flow in the bilateral putamen in patients undergoing hemodialysis

Association between susceptibility value and cerebral blood flow in the bilateral putamen in patients undergoing hemodialysis

Levodopa Impairs the Energy Metabolism of the Basal Ganglia In Vivo

A Mouse Model to Test Novel Therapeutics for Parkinson's Disease: an Update on the Thy1-aSyn (“line 61”) Mice

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