Emerging neuroprotective effect of metformin in Parkinson’s disease: A molecular crosstalk

Paudel, Yam Nath; Angelopoulou, Efthalia; Piperi, Christina; Shaikh, Mohd Farooq; Othman, Iekhsan

doi:10.1016/j.phrs.2019.104593

Cited by 63 publications

(47 citation statements)

References 118 publications

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“…In support of this hypothesis, treatment with the AMPK activator metformin was sufficient to reduce PFF-induced pS129 α-syn pathology in neurons (SI Appendix, Fig. S10 B and C), consistent with previous findings showing protective effects of metformin on pS129 α-syn levels in other PD models (48,49).…”

Section: Itpkb Inhibition Increases α-Syn Pathology Induced By Preformedsupporting

confidence: 90%

“…We show that AMPK activity negatively correlates with both mTOR activity and α-syn pathology in primary neurons, suggesting AMPK activation as a potential therapeutic strategy in PD capable of normalizing cellular metabolism, reducing neuropathology, or both. In support of this hypothesis, the AMPK activator metformin, which is an approved therapy for diabetes mellitus, has been shown to be protective in multiple cellular and animal models of PD (48,49,76,77), an observation that we now extend to the neuronal PFF α-syn seeding model. These findings may be therapeutically relevant due to the increased incidence of PD in patients with diabetes (78).…”

Section: Discussionmentioning

confidence: 67%

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The Parkinson’s disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release

Apicco

Shlevkov

Nezich

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) is a ubiquitously expressed lipid kinase that inactivates IP3, a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). Genome-wide association studies have identified common variants in the ITPKB gene locus associated with reduced risk of sporadic Parkinson’s disease (PD). Here, we investigate whether ITPKB activity or expression level impacts PD phenotypes in cellular and animal models. In primary neurons, knockdown or pharmacological inhibition of ITPKB increased levels of phosphorylated, insoluble α-synuclein pathology following treatment with α-synuclein preformed fibrils (PFFs). Conversely, ITPKB overexpression reduced PFF-induced α-synuclein aggregation. We also demonstrate that ITPKB inhibition or knockdown increases intracellular calcium levels in neurons, leading to an accumulation of calcium in mitochondria that increases respiration and inhibits the initiation of autophagy, suggesting that ITPKB regulates α-synuclein pathology by inhibiting ER-to-mitochondria calcium transport. Furthermore, the effects of ITPKB on mitochondrial calcium and respiration were prevented by pretreatment with pharmacological inhibitors of the mitochondrial calcium uniporter complex, which was also sufficient to reduce α-synuclein pathology in PFF-treated neurons. Taken together, these results identify ITPKB as a negative regulator of α-synuclein aggregation and highlight modulation of ER-to-mitochondria calcium flux as a therapeutic strategy for the treatment of sporadic PD.

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Section: Itpkb Inhibition Increases α-Syn Pathology Induced By Preformedsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 67%

The Parkinson’s disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release

Apicco

Shlevkov

Nezich

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Metformin was found to decrease phosphor-Ser129 α-synuclein, 31 as well as rescue TH-positive dopaminergic neurons by inhibiting several proinflammatory markers and brain oxidative stress levels via autophagy and mitochondria Reactive Oxygen Species (ROS) clearance. 32 33 Although metformin was reported to exert a neuroprotective role in most of the PD animal models induced by neurotoxins, 34 it failed to improve motor coordination/balance 35 and even exacerbated dopaminergic damage in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 36 which was the most frequently used neurotoxin to evaluate the effect of metformin on models of PD. Another study reported that the overactivation of AMPK might lead to the accumulation of α-syn.…”

Section: Discussionmentioning

confidence: 99%

Association between metformin and neurodegenerative diseases of observational studies: systematic review and meta-analysis

Ping

Jiang

2020

BMJ Open Diab Res Care

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Background and aimsAging becomes a growing global concern with an increased risk of neurodegenerative diseases (NDs) that mainly consist of cognitive decline and Parkinson disease (PD). As the most commonly prescribed antidiabetic drug, metformin has been shown to have inconsistent roles in the incidence of NDs. We performed a systematic review and meta-analysis of observational studies to evaluate the effect of metformin exposure on onset of NDs.MethodsThe observational studies that investigated the associations between metformin and the incidence of NDs were searched in MEDLINE, Embase and Cochrane Library databases. A random-effect model was performed using STATA to calculate the combined ORs.ResultsIn total, 23 comparisons out of 19 studies with 285 966 participants were included. Meta-analysis found there was no significant effect on incidence of all the subtypes of NDs with metformin exposure (OR 1.04, 95% CI 0.92 to 1.17). However, metformin monotherapy was associated with a significantly increased risk of PD incidence compared with non-metformin users or glitazone users (OR 1.66, 95% CI 1.14 to 2.42).ConclusionMetformin has failed to demonstrate a beneficial effect on NDs. In addition, it may increase the risk of PD development. In light of current results, how metformin would impact NDs, especially the potential risk of PD, needs to be scrutinized. The underlying mechanisms are vital to achieve some more profound understanding on the regimen.Trial registration numberCRD 42019133285.

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“…Parkinson's disease (PD) is the most common neurodegenerative movement disorder affecting approximately 1-2% of the population above the age of 65 years [1]. The key pathological hallmarks of the disease involve the intracellular accumulation of α-synuclein in the form of Lewy bodies and Lewy dendrites, as well as the dopaminergic neuronal loss in the substantia pars compacta (SNpc) resulting in nigrostriatal degeneration [1][2][3]. However, its pathology progresses gradually from the brainstem to cortical regions [4].…”

Section: Introductionmentioning

confidence: 99%

“…Lewy dendrites, as well as the dopaminergic neuronal loss in the substantia pars compacta (SNpc) resulting in nigrostriatal degeneration [1][2][3]. However, its pathology progresses gradually from the brainstem to cortical regions [4].…”

Section: Introductionmentioning

confidence: 99%

Lymphocyte-Activation Gene 3 (LAG3) Protein as a Possible Therapeutic Target for Parkinson’s Disease: Molecular Mechanisms Connecting Neuroinflammation to α-Synuclein Spreading Pathology

Angelopoulou

Paudel

Clara

et al. 2020

Biology

Self Cite

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Parkinson’s disease (PD) is the most common neurodegenerative movement disorder without any objective biomarker available to date. Increasing evidence highlights the critical role of neuroinflammation, including T cell responses, and spreading of aggregated α-synuclein in PD progression. Lymphocyte-activation gene 3 (LAG3) belongs to the immunoglobulin (Ig) superfamily expressed by peripheral immune cells, microglia and neurons and plays a key role in T cell regulation. The role of LAG3 has been extensively investigated in several human cancers, whereas until recently, the role of LAG3 in the central nervous system (CNS) has been largely unknown. Accumulating evidence highlights the potential role of LAG3 in PD pathogenesis, mainly by binding to α-synuclein fibrils and affecting its endocytosis and intercellular transmission, which sheds more light on the connection between immune dysregulation and α-synuclein spreading pathology. Serum and cerebrospinal fluid (CSF) soluble LAG3 (sLAG3) levels have been demonstrated to be potentially associated with PD development and clinical phenotype, suggesting that sLAG3 could represent an emerging PD biomarker. Specific single nucleotide polymorphisms (SNPs) of the LAG3 gene have been also related to PD occurrence especially in the female population, enlightening the pathophysiological background of gender-related PD clinical differences. Given also the ongoing clinical trials investigating various LAG3-targeting strategies in human diseases, new opportunities are being developed for PD treatment research. In this review, we discuss recent preclinical and clinical evidence on the role of LAG3 in PD pathogenesis and biomarker potential, aiming to elucidate its underlying molecular mechanisms.

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Emerging neuroprotective effect of metformin in Parkinson’s disease: A molecular crosstalk

Cited by 63 publications

References 118 publications

The Parkinson’s disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release

The Parkinson’s disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release

Association between metformin and neurodegenerative diseases of observational studies: systematic review and meta-analysis

Lymphocyte-Activation Gene 3 (LAG3) Protein as a Possible Therapeutic Target for Parkinson’s Disease: Molecular Mechanisms Connecting Neuroinflammation to α-Synuclein Spreading Pathology

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