PGC-1s in the Spotlight with Parkinson’s Disease

Piccinin, Elena; Sardanelli, Anna Maria; Seibel, Peter; Moschetta, Antonio; Cocco, Tiziana; Villani, Gaetano

doi:10.3390/ijms22073487

Cited by 48 publications

(28 citation statements)

References 182 publications

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“…PGC-1α is widely distributed in tissues that necessitate an enormous amount of energy [ 196 ]. The relationship between PD and variations in mitochondrial equilibrium has been observed [ 197 ]. Several investigations have been conducted in order to adequately scrutinize the involvement of PGC-1α in PD.…”

Section: Experimental Studies Portraying the Deep Insights Into The Neuroprotective Role Of Ppar Agonists In Pdmentioning

confidence: 99%

Elucidating the Neuroprotective Role of PPARs in Parkinson’s Disease: A Neoteric and Prospective Target

Behl

Madaan

Sehgal

et al. 2021

IJMS

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One of the utmost frequently emerging neurodegenerative diseases, Parkinson’s disease (PD) must be comprehended through the forfeit of dopamine (DA)-generating nerve cells in the substantia nigra pars compacta (SN-PC). The etiology and pathogenesis underlying the emergence of PD is still obscure. However, expanding corroboration encourages the involvement of genetic and environmental factors in the etiology of PD. The destruction of numerous cellular components, namely oxidative stress, ubiquitin-proteasome system (UPS) dysfunction, autophagy-lysosome system dysfunction, neuroinflammation and programmed cell death, and mitochondrial dysfunction partake in the pathogenesis of PD. Present-day pharmacotherapy can alleviate the manifestations, but no therapy has been demonstrated to cease disease progression. Peroxisome proliferator-activated receptors (PPARs) are ligand-directed transcription factors pertaining to the class of nuclear hormone receptors (NHR), and are implicated in the modulation of mitochondrial operation, inflammation, wound healing, redox equilibrium, and metabolism of blood sugar and lipids. Numerous PPAR agonists have been recognized to safeguard nerve cells from oxidative destruction, inflammation, and programmed cell death in PD and other neurodegenerative diseases. Additionally, various investigations suggest that regular administration of PPAR-activating non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, indomethacin), and leukotriene receptor antagonists (montelukast) were related to the de-escalated evolution of neurodegenerative diseases. The present review elucidates the emerging evidence enlightening the neuroprotective outcomes of PPAR agonists in in vivo and in vitro models experiencing PD. Existing articles up to the present were procured through PubMed, MEDLINE, etc., utilizing specific keywords spotlighted in this review. Furthermore, the authors aim to provide insight into the neuroprotective actions of PPAR agonists by outlining the pharmacological mechanism. As a conclusion, PPAR agonists exhibit neuroprotection through modulating the expression of a group of genes implicated in cellular survival pathways, and may be a propitious target in the therapy of incapacitating neurodegenerative diseases like PD.

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Section: Experimental Studies Portraying the Deep Insights Into The Neuroprotective Role Of Ppar Agonists In Pdmentioning

confidence: 99%

Elucidating the Neuroprotective Role of PPARs in Parkinson’s Disease: A Neoteric and Prospective Target

Behl

Madaan

Sehgal

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…9B, E, F). The marked impact of NAAA deletion on cellular bioenergetics pathways led us to hypothesize that members of the PGC-1 family, which are crucial upstream regulators of those pathways and have been implicated in dopamine neuron survival and the pathogenesis of PD (Jiang et al , 2016; Zheng et al , 2010; Su et al , 2015; Piccinin et al , 2021), might be involved. Supporting this conclusion, a closer inspection of the proteomics data identified type-ß peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1ß) as one of the proteins deregulated by 6-OHDA (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…10 C). PGC-1α and PGC-1ß serve pivotal functions in metabolic control (Handschin & Spiegelman 2006) and, importantly, have been implicated in dopamine neuron survival (Jiang et al , 2016) and the pathogenesis of PD (Zheng et al , 2010; Su et al , 2015; Piccinin et al , 2021; Das et al, 2021; Jamwal et al , 2021). Similar roles have been ascribed to PPAR-α (Gottschalk et al , 2021; Avagliano et al , 2016), PEA’s primary receptor and obligatory PGC-1α partner (Handschin & Spiegelman 2006).…”

Section: Discussionmentioning

confidence: 99%

Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of Parkinson’s disease

Palese

Pontis

Realini

et al. 2022

Preprint

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The lysosomal cysteine hydrolase N-acylethanolamine acid amidase (NAAA) deactivates the lipid-derived mediator palmitoylethanolamide (PEA), an endogenous PPAR-alpha agonist that is critically involved in the control of inflammation and nociception. In this study, we asked whether NAAA-regulated PEA signaling might contribute to the pathogenesis of Parkinson's disease (PD), a neurodegenerative disorder characterized by progressive loss of nigrostriatal dopamine neurons. Analyses of postmortem brain cortex and premortem blood-derived exosomes found elevated levels of NAAA expression in persons with PD compared to age-matched controls. Furthermore, in vitro experiments showed that the dopaminergic neurotoxins, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), enhanced NAAA expression and lowered PEA content in human SH-SY5Y cells. A similar effect was observed in dopamine neurons and, subsequently, in microglia following 6-OHDA injection in mice. Importantly, deletion of the Naaa gene or pharmacological inhibition of NAAA activity markedly attenuated both dopamine neuron death and parkinsonian symptoms in mice treated with 6-OHDA or MPTP. The results identify NAAA-regulated PEA signaling as a control node for dopaminergic neuron survival and a potential target for therapeutic intervention in PD.

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“…Changes in mitochondrial biogenesis and dynamics were found to be directly linked to PD onset. This led to a thorough examination of the role of PGC-1s in the onset and progression of PD [ 173 ]. In vivo studies on transgenic mouse models of PD in which PGC-1α was either knocked out or genetically disrupted revealed an enhanced vulnerability to the neurodegenerative effects of MPTP and kainic acid, due to a lack of PGC-1α-dependent induction of the antioxidant response [ 174 ].…”

Section: Novel Therapeutic Strategies In Pd Managementmentioning

confidence: 99%

Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update

2022

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Parkinson’s disease (PD) is a neurodegenerative disorder pathologically distinguished by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Muscle rigidity, tremor, and bradykinesia are all clinical motor hallmarks of PD. Several pathways have been implicated in PD etiology, including mitochondrial dysfunction, impaired protein clearance, and neuroinflammation, but how these factors interact remains incompletely understood. Although many breakthroughs in PD therapy have been accomplished, there is currently no cure for PD, only trials to alleviate the related motor symptoms. To reduce or stop the clinical progression and mobility impairment, a disease-modifying approach that can directly target the etiology rather than offering symptomatic alleviation remains a major unmet clinical need in the management of PD. In this review, we briefly introduce current treatments and pathophysiology of PD. In addition, we address the novel innovative therapeutic targets for PD therapy, including α-synuclein, autophagy, neurodegeneration, neuroinflammation, and others. Several immunomodulatory approaches and stem cell research currently in clinical trials with PD patients are also discussed. Moreover, preclinical studies and clinical trials evaluating the efficacy of novel and repurposed therapeutic agents and their pragmatic applications with encouraging outcomes are summarized. Finally, molecular biomarkers under active investigation are presented as potentially valuable tools for early PD diagnosis.

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PGC-1s in the Spotlight with Parkinson’s Disease

Cited by 48 publications

References 182 publications

Elucidating the Neuroprotective Role of PPARs in Parkinson’s Disease: A Neoteric and Prospective Target

Elucidating the Neuroprotective Role of PPARs in Parkinson’s Disease: A Neoteric and Prospective Target

Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of Parkinson’s disease

Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update

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