Mutual exacerbation of peroxisome proliferator‐activated receptor γ coactivator 1α deregulation and α‐synuclein oligomerization

Eschbach, Judith; Einem, Bjoern von; Müller, Kathrin; Bayer, Hanna; Scheffold, Annika; Morrison, Brad; Rudolph, K. Lenhard; Thal, Dietmar Rudolf; Witting, PD Anke; Weydt, Patrick; Otto, Markus; Fauler, Michael; Liss, Birgit; McLean, Pamela J.; Spada, Albert R. La; Ludolph, Albert C.; Weishaupt, Jochen H.; Danzer, Karin M

doi:10.1002/ana.24294

Cited by 115 publications

(93 citation statements)

References 104 publications

(226 reference statements)

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“…Dose selection was based on the preclinical data showing a neuroprotective effect within 15–45 mg/kg human dose equivalent 11–14 and these doses falling within the FDA-approved range for use in the human diabetic population. Participants and investigators were masked to treatment group.…”

Section: Methodsmentioning

confidence: 99%

“…10 PPAR-γ coactivator 1-α (PGC-1α) is a transcriptional coactivator that controls mitochondrial biogenesis and oxidative stress. 11 Preclinical data in rodent and primate Parkinson's disease models showed good CNS penetration of pioglitazone and neuroprotective effects at a dose in animals that is the equivalent of the FDA-approved dose for use in human beings. 11–14 …”

Section: Introductionmentioning

confidence: 99%

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Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial

2015

The Lancet Neurology

224

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Summary Background A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Methods Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0.10. The study is registered at ClinicalTrials.gov, number NCT01280123. Findings 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4.42 (95% CI 2.55–6.28) for 15 mg pioglitazone, 5.13 (95% CI 3.17–7.08) for 45 mg pioglitazone, and 6.25 (95% CI 4.35–8.15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was −1.83 (80% CI −3.56 to −0.10) and the null hypothesis could not be rejected (p=0.19). The mean difference between the 45 mg and placebo groups was −1.12 (80% CI −2.93 to 0.69) and the null hypothesis was rejected in favour of futility (p=0.09). Planned sensitivity analyses of the primary outcome, using last value carried forward (LVCF) to handle missing data and using the completers' only sample, suggested that the 15 mg dose is also futile (p=0.09 for LVCF, p=0.09 for completers) but failed to reject the null hypothesis for the 45 mg dose (p=0.12 for LVCF, p=0.19 for completers). Six serious adverse events occurred in the 15 mg group, nine in the 45 mg group, and three in the placebo group; none were thought to be definitely or probably related to the study interventions. Interpretation These findings suggest that pioglitazone at the doses studied here is unlikely to modify progression in early Parkinson's disease. Further study of pioglitazone in a larger trial in patients with Parkinson's disease is not recommended. Funding National Institute of Neurological Disorders and Stroke.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial

2015

The Lancet Neurology

224

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“…PGC-1α is essential in normal mitochondrial functioning and its deficiency may contribute to neurodegeneration, while its stimulation demonstrated to be neuroprotective in certain models (Breidert et al, 2002;Dehmer et al, 2004;Eschbach et al, 2015;Mudo et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the loss of that PGC-1α enhances the vulnerability of SN pars compacta dopaminergic neurons to α-synuclein toxicity (Ciron et al, 2015). These data suggest that PGC-1α downregulation and α-synuclein oligomerization form a vicious circle (Eschbach et al, 2015). Similarly to PD, certain mutations in amyotrophic lateral sclerosis inhibit the expression of CNS-specific isoforms, indicating this as a common finding in neurodegeneration (Bayer et al, 2017).…”

mentioning

confidence: 99%

“…The novel CNS-specific isoforms originated from a new promoter located 587 kb upstream of exon 2 (Choi et al, 2013;Soyal et al, 2012). A recent study demonstrated that both PGC-1α reference gene and CNS-PGC-1α are downregulated in human PD brain and in experimental models with α-synuclein oligomerization and that the pharmacological activation or genetic overexpression of PGC-1α reference gene reduced α-synuclein oligomerization and toxicity (Eschbach et al, 2015). In contrast, the loss of that PGC-1α enhances the vulnerability of SN pars compacta dopaminergic neurons to α-synuclein toxicity (Ciron et al, 2015).…”

mentioning

confidence: 99%

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Effect of MPTP on mRNA expression of PGC-1α in mouse brain

et al. 2017

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The peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC-1α) is a key regulator of mitochondrial biogenesis, respiration and adaptive thermogenesis. Beside the full-length protein (FL-PGC-1α), several other functionally active PGC-1α isoforms were identified as a result of alternative splicing (e.g., N-truncated PGC-1α; NT-PGC-1α) or alternative promoter usage (e.g., central nervous system-specific PGC-1α isoforms; CNS-PGC-1α). The achievement of neuroprotection via the CNS-targeted pharmacological stimulation is limited due to the poor penetration of the blood brain barrier (BBB) by the proposed pharmaceutical agents, so preconditioning emerged as another option. The current study aimed at the examination of how the expression levels of FL-, NT-, CNS-and reference PGC-1α isoforms change in different brain regions following various 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment regimens, including the chronic low dose treatment for preconditioning. Ninety minutes following the acute treatment regimen, the expression level of FL-, NT-and CNS-PGC-1α isoforms increased significantly in the striatum, cortex and cerebellum. However, this elevation was diminished 7 days following the last MPTP injection in this acute treatment regimen. The chronic low dose administration of MPTP, which did not cause significant toxic effect in light of the relatively unaltered dopamine levels, neither resulted in any significant change of PGC-1α expression as well. The elevation of PGC-1α levels following acute treatment may demonstrate a short-term compensatory mechanism against the mitochondrial damage induced by the complex I inhibitor MPTP. However, drug-induced preconditioning by chronic low dose MPTP seems not to induce protective responses via the PGC-1α system.

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Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases

et al. 2016

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The term oligomeropathies defines the neurodegenerative disorders associated with protein misfolding, where small soluble aggregates (oligomers 4-200 KDa) are the cause of neuronal dysfunction and are responsible for spreading the pathology. The ability of these soluble β-sheet conformers to induce neuronal damage has been investigated in direct challenge with the monomeric and fibrillary structures, showing that only the oligomeric species affected the neurons. β amyloid oligomers were initially purified from Alzheimer brains and obtained using synthetic peptides. Together with the neuronal death, synaptic dysfunction, loss of spines, and LTP impairment were seen with the direct application of β amyloid oligomers. Similar results have been described with proteins associated with other neurodegenerative disorders. The biological activities of oligomeric forms of α synuclein have been described in Parkinson's disease and Lewy body dementia. Detrimental effects have been associated with the oligomeric forms of prion, tau, and huntingtin, the key proteins in prion diseases, frontotemporal dementia, and Huntington's disease, respectively. The molecular mechanisms of the oligomer-related toxic effects can be summarized under three headings: nonspecific perturbance of cellular and intracellular membranes, specific interaction with various cellular entities, and amyloid pore channel formation. To characterize and distinguish oligomer actions better, we compared the ability of β amyloid and α synuclein oligomers to induce cognitive impairment when applied directly into the brain in the same acute mouse model. We also investigated the role of inflammatory components. © 2016 International Parkinson and Movement Disorder Society.

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Mutual exacerbation of peroxisome proliferator‐activated receptor γ coactivator 1α deregulation and α‐synuclein oligomerization

Cited by 115 publications

References 104 publications

Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial

Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial

Effect of MPTP on mRNA expression of PGC-1α in mouse brain

Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases

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