mTOR Signaling in Parkinson’s Disease

Lan, Ai ping; Chen, Jun; Zhao, Ye; Chai, Zhifang; Hu, Yi

doi:10.1007/s12017-016-8417-7

Cited by 74 publications

(58 citation statements)

References 133 publications

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“…To achieve this balance, mTORC inhibition is being explored as a possible treatment route for PD. Rapamycin has been shown to overcome dyskinesia in mice, a major side effect of treatment with L-DOPA, without interfering with the therapeutic effects of L-DOPA [126], while a number of other studies have also demonstrated benefits of rapamycin use in PD (reviewed in [127]). As in AD, other mTOR pathway factors such as GS3K might present therapeutic targets, particularly as lysosomal function appears important.…”

Section: Parkinson's Diseasementioning

confidence: 99%

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

Walters

Cox

2018

Preprint

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Chronological age represents the greatest risk factor for many life-threatening diseases including neurodegeneration, cancer and cardiovascular disease; ageing also increases susceptibility to infectious disease. Current therapies that effectively tackle individual diseases may have little impact on the overall healthspan of older individuals, who would still be vulnerable to other age-related pathologies. However, recent progress in ageing research has highlighted the accumulation of senescent cells with chronological age as a probable underlying cause of pathological ageing. Cellular senescence is an essentially irreversible proliferation arrest mechanism that has important roles in development, wound healing and preventing cancer, but it may limit tissue function and cause widespread inflammation with age. The serine/threonine kinase mTOR is a regulatory nexus heavily implicated in both ageing and senescence. Excitingly, a growing body of research has highlighted rapamycin and other mTOR inhibitors as promising treatments for a broad spectrum of age-related pathologies, including neurodegeneration, cancer, immunosenescence, osteoporosis, rheumatoid arthritis, age-related blindness, diabetic nephropathy, muscular dystrophy, and cardiovascular disease. In this review, we assess the use of mTOR inhibitors to treat age-related pathologies, discuss possible molecular mechanisms of action where evidence is available, and consider strategies to minimize undesirable side effects. We also emphasize the urgent need for reliable, non-invasive biomarkers of senescence and biological ageing to better monitor the efficacy of any healthy ageing therapy.

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Section: Parkinson's Diseasementioning

confidence: 99%

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

Walters

Cox

2018

Preprint

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“…Rapamycin has been shown to overcome dyskinesia in mice, which is a major side effect of treatment with L-DOPA, without interfering with the therapeutic effects of L-DOPA [149], while a number of other studies have also demonstrated benefits of rapamycin use in PD (reviewed in [150]). As in AD, other mTOR pathway factors, such as GSK3, might present therapeutic targets, particularly as lysosomal function appears important.…”

Section: Ageing and Age-related Pathologies Amenable To Treatment mentioning

confidence: 99%

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

Walters

Cox

2018

IJMS

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Chronological age represents the greatest risk factor for many life-threatening diseases, including neurodegeneration, cancer, and cardiovascular disease; ageing also increases susceptibility to infectious disease. Current efforts to tackle individual diseases may have little impact on the overall healthspan of older individuals, who would still be vulnerable to other age-related pathologies. However, recent progress in ageing research has highlighted the accumulation of senescent cells with chronological age as a probable underlying cause of pathological ageing. Cellular senescence is an essentially irreversible proliferation arrest mechanism that has important roles in development, wound healing, and preventing cancer, but it may limit tissue function and cause widespread inflammation with age. The serine/threonine kinase mTOR (mechanistic target of rapamycin) is a regulatory nexus that is heavily implicated in both ageing and senescence. Excitingly, a growing body of research has highlighted rapamycin and other mTOR inhibitors as promising treatments for a broad spectrum of age-related pathologies, including neurodegeneration, cancer, immunosenescence, osteoporosis, rheumatoid arthritis, age-related blindness, diabetic nephropathy, muscular dystrophy, and cardiovascular disease. In this review, we assess the use of mTOR inhibitors to treat age-related pathologies, discuss possible molecular mechanisms of action where evidence is available, and consider strategies to minimize undesirable side effects. We also emphasize the urgent need for reliable, non-invasive biomarkers of senescence and biological ageing to better monitor the efficacy of any healthy ageing therapy.

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“…mTORC2 signaling has also been implicated in reward tolerance to opiate drugs via changes in VTA neuron size and excitability (Mazei-Robison et al, 2011). mTORC1 signaling has also been studied in the context of PD, where mTOR activation has been shown to acutely promote DA neuron survival, possibly via increased protein synthesis at the site of injury and/or inhibition of autophagic processes (Cheng et al, 2011;Diaz-Ruiz et al, 2009;Domanskyi et al, 2011;Kim et al, 2012;Lan et al, 2017;Malagelada et al, 2010;Xu et al, 2014;Zhou et al, 2015). Here, we build upon this literature and show, for the first time, that chronic developmental activation of mTORC1 signaling arising from Tsc1 loss leads to altered DA neuron structure at multiple levels, inducing somatic, dendritic, and axonal hypertrophy.…”

Section: Mtor Signaling In Da Neuronsmentioning

confidence: 99%

Tsc1-mTOR signaling controls the structure and function of midbrain dopamine neurons

Kosillo¹,

Doig

Ahmed³

et al. 2018

Preprint

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mTOR complex 1 (mTORC1) is a central coordinator of cell growth and metabolism. Mutations in regulators of mTORC1 cause syndromic disorders with a high prevalence of cognitive and psychiatric conditions. To elucidate the cellular origins of these manifestations, we conditionally deleted the gene encoding the mTORC1 negative regulator Tsc1 from mouse midbrain dopamine neurons, which modulate motor, affective, and cognitive behaviors that are frequently affected in psychiatric disorders. Loss of Tsc1 and constitutive activation of mTORC1 strongly impacted the properties of dopamine neurons, causing somatodendritic hypertrophy, reduced intrinsic excitability, altered axon terminal ultrastructure, and severely impaired dopamine release. These perturbations were associated with selective deficits in cognitive flexibility, which could be prevented by genetic reduction of the obligatory mTORC1 protein Raptor. Our results establish a critical role for mTORC1 in setting the functional properties of midbrain dopamine neurons, and indicate that dopaminergic dysfunction may underlie cognitive inflexibility in mTOR-related syndromes.

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mTOR Signaling in Parkinson’s Disease

Cited by 74 publications

References 133 publications

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

Tsc1-mTOR signaling controls the structure and function of midbrain dopamine neurons

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