Parallel neurodegenerative phenotypes in sporadic Parkinson’s disease fibroblasts and midbrain dopamine neurons

Corenblum, Mandi J.; McRobbie-Johnson, Aiden; Carruth, Emma; Bernard, Kelsey; Luo, Moulun; Mandarino, Lawrence J.; Peterson, Steven L.; Sans-Fuentes, Maria; Billheimer, Dean; Maley, Timothy; Eggers, Erika D.; Madhavan, Lalitha

doi:10.1016/j.pneurobio.2023.102501

Cited by 5 publications

(2 citation statements)

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“…Fibroblasts serve as a robust model for the study of numerous diseases, as evidenced by numerous studies conducted over the years [26,[62][63][64][65][66][67][68][69][70]. In this work, we establish that fibroblasts derived from patients with mutations in the GFM1 gene constitute a valuable experimental model for investigating mitochondrial diseases.…”

Section: Discussionmentioning

confidence: 90%

Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation

Cilleros-Holgado,

Gómez-Fernández,

Piñero-Pérez

et al. 2024

Biomolecules

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Primary mitochondrial diseases result from mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) genes, encoding proteins crucial for mitochondrial structure or function. Given that few disease-specific therapies are available for mitochondrial diseases, novel treatments to reverse mitochondrial dysfunction are necessary. In this work, we explored new therapeutic options in mitochondrial diseases using fibroblasts and induced neurons derived from patients with mutations in the GFM1 gene. This gene encodes the essential mitochondrial translation elongation factor G1 involved in mitochondrial protein synthesis. Due to the severe mitochondrial defect, mutant GFM1 fibroblasts cannot survive in galactose medium, making them an ideal screening model to test the effectiveness of pharmacological compounds. We found that the combination of polydatin and nicotinamide enabled the survival of mutant GFM1 fibroblasts in stress medium. We also demonstrated that polydatin and nicotinamide upregulated the mitochondrial Unfolded Protein Response (mtUPR), especially the SIRT3 pathway. Activation of mtUPR partially restored mitochondrial protein synthesis and expression, as well as improved cellular bioenergetics. Furthermore, we confirmed the positive effect of the treatment in GFM1 mutant induced neurons obtained by direct reprogramming from patient fibroblasts. Overall, we provide compelling evidence that mtUPR activation is a promising therapeutic strategy for GFM1 mutations.

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Section: Discussionmentioning

confidence: 90%

Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation

Cilleros-Holgado,

Gómez-Fernández,

Piñero-Pérez

et al. 2024

Biomolecules

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“…Similarly, Ambrosi and colleagues 22 observed reduced maximal respiration and rotenonesensitive respiration levels in the same patients. Corenblum and colleagues 23 recently confirmed concurrent respiratory dysfunction and network fragmentation in fibroblasts from late-onset sporadic PD and induced pluripotent stem cells (iPSC)-based dopamingeric neurons from the same patients. Although some variations in mitochondrial respiration were noted between the two cell types, possibly because of fibroblasts' compensatory capacity for mitochondrial issues, this study suggests that peripheral tissue dysfunction may be linked to brain abnormalities in patients.…”

Section: Discussionmentioning

confidence: 91%

Impaired Mitochondrial Respiration in REM‐Sleep Behavior Disorder: A Biomarker of Parkinson's Disease?

Ongari,

Ghezzi,

Di Martino

et al. 2023

Movement Disorders

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BackgroundIdiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is associated with prodromal Parkinson's disease (PD), but the mechanisms linking phenoconversion of iRBD to PD have not yet been clarified. Considering the association between mitochondrial dysfunction and sleep disturbances in PD, we explored mitochondrial activity in fibroblasts derived from iRBD patients to identify a biochemical profile that could mark the presence of impending neurodegeneration.MethodsThe study involved 28 participants, divided into three groups: patients diagnosed with iRBD, PD patients converted from iRBD (RBD‐PD), and healthy controls. We performed a comprehensive assessment of mitochondrial function, including an examination of mitochondrial morphology, analysis of mitochondrial protein expression levels by western blot, and measurement of mitochondrial respiration using the Seahorse XFe24 analyzer.ResultsIn basal conditions, mitochondrial respiration did not differ between iRBD and control fibroblasts, but when cells were challenged with a higher energy demand, iRBD fibroblasts exhibited a significant (P = 0.006) drop in maximal and spare respiration compared to controls. Interestingly, RBD‐PD patients showed the same alterations with a further significant reduction in oxygen consumption linked to adenosine triphosphate production (P = 0.032). Moreover, RBD‐PD patients exhibited a significant decrease in protein levels of complexes III (P = 0.02) and V (P = 0.002) compared to controls, along with fragmentation of the mitochondrial network. iRBD patients showed similar, but milder alterations.ConclusionsAltogether, these findings suggest that mitochondrial dysfunctions in individuals with iRBD might predispose to worsening of the bioenergetic profile observed in RBD‐PD patients, highlighting these alterations as potential predictors of phenoconversion to PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Impaired neurogenesis and synaptogenesis in iPSC-derived Parkinson’s patient cortical neurons with D620N VPS35 mutation

Scheller,

Lee,

Seibler

et al. 2024

Preprint

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Presynaptic dysfunction is an important early process in the pathophysiology of Parkinson’s disease (PD) that drives disease progression. To gain insight into the intrinsic synapse impairment in PD, we performed comprehensive electrophysiological and morphological analysis of iPSC-derived cortical neurons derived from PD patients with the VPS35-D620N mutation. Our findings reveal significant impairment in neurogenesis and synaptogenesis within individual patient neurons, culminating to synaptic dysfunction even in the absence of neuronal interactions. The neurons exhibited significantly reduced synaptic responsiveness, fewer synapse and decreased dendritic length and complexity. Thus, the VPS35-D620N mutation in human cortical neurons independently can cause pathophysiology via synaptic dysfunction. Our study highlights the urgent need to develop disease-modifying therapies aimed at preserving synaptic function in PD.

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Parallel neurodegenerative phenotypes in sporadic Parkinson’s disease fibroblasts and midbrain dopamine neurons

Cited by 5 publications

References 46 publications

Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation

Polydatin and Nicotinamide Rescue the Cellular Phenotype of Mitochondrial Diseases by Mitochondrial Unfolded Protein Response (mtUPR) Activation

Impaired Mitochondrial Respiration in REM‐Sleep Behavior Disorder: A Biomarker of Parkinson's Disease?

Impaired neurogenesis and synaptogenesis in iPSC-derived Parkinson’s patient cortical neurons with D620N VPS35 mutation

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