mTORC1-Dependent Protein and Parkinson’s Disease: A Mendelian Randomization Study

Tan, Cheng; Ai, Jianzhong; Zhu, Ye

doi:10.3390/brainsci13040536

Cited by 4 publications

(1 citation statement)

References 45 publications

(49 reference statements)

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“…Previous research employed genetic variants that modulate the expression of mTORC1's downstream targets regulating protein translation to study their effect on type 2 diabetes, rheumatic fever, Alzheimer's disease, Parkinson's disease, and cataract formation [32][33][34][35][36] . These studies utilised moderately associated (p-value < 5 × 10 -6…”

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confidence: 99%

Evaluating the life-extending potential and safety profile of rapamycin: a Mendelian Randomization study of the mTOR pathway

Sobczyk,

Gaunt

2023

Preprint

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ObjectiveThe mechanistic target of rapamycin (mTOR) pathway plays an integral role in cellular metabolism, growth, and aging. While rapamycin and its analogs inhibit the mTOR pathway, extending lifespan in various organisms, the long-term safety and efficacy of these compounds in humans remain understudied.MethodsUtilizing two mTOR expression QTL instruments derived from the eQTLgen and MetaBrain studies, we sought to explore the potential causal relationship between mTOR expression inhibition in blood and brain cortex (mimicking chronic rapamycin use), and its effects on longevity, cardiometabolic disease, prostate cancer and anthropometric risk factors. Subsequently, we extended the selection of instruments to 47 other members of the mTOR pathway. To complement this Mendelian randomization (MR) evidence, we conducted genetic colocalisation and sampling-based enrichment testing.ResultsOur findings suggest that genetically proxied mTOR inhibition may increase the odds of attaining top 1% longest lifespan in the population (OR=1.24, OR95%CI=1-1.53, p-value=0.048). Moreover, mTOR inhibition significantly reduced body mass index (BMI), basal metabolic rate (BMR), height, and age at menopause, while increasing bone mineral density. Interestingly, there was generally little evidence linking mTOR inhibition to cardiovascular disease incidence, with the exception of weak evidence for a protective effect against heart failure (OR=0.94, OR95%CI=0.89-0.99, p-value=0.039). Chronic mTOR inhibition did not causally affect prostate cancer incidence but increased the risk of developing type 2 diabetes. A higher-than-expected (p-value = 0.05) number of genes in the mTOR pathway were causally associated with BMR.ConclusionsThis study highlights the potential lifespan-extending effects of mTOR inhibition and its significant influence on metabolic risk factors and disease. Members of the mTOR complex, especially mTORC1, play a disproportionate role in influencing BMR and BMI, which provides valuable insight for potential therapeutic target development.

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confidence: 99%

Evaluating the life-extending potential and safety profile of rapamycin: a Mendelian Randomization study of the mTOR pathway

Sobczyk,

Gaunt

2023

Preprint

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The autophagy proteome in the brain

Ito‐Silva,

Smith,

Martins‐de‐Souza

2024

Journal of Neurochemistry

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As one of the most important cellular housekeepers, autophagy directly affects cellular health, homeostasis, and function. Even though the mechanisms behind autophagy are well described, how molecular alterations and dysfunctions can lead to pathology in disease contexts still demands deeper investigation. Proteomics is a widely employed tool used to investigate molecular alterations associated with pathological states and has proven useful in identifying alterations in protein expression levels and post‐translational modifications in autophagy. In this narrative review, we expand on the molecular mechanisms behind autophagy and its regulation, and further compile recent literature associating autophagy disturbances in context of brain disorders, utilizing discoveries from varying models and species from rodents and cellular models to human post‐mortem brain samples. To outline, the canonical pathways of autophagy, the effects of post‐translational modifications on regulating each step of autophagy, and the future directions of proteomics in autophagy will be discussed. We further aim to suggest how advancing proteomics can help further unveil molecular mechanisms with regard to neurological disorders.image

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The impact of aging and oxidative stress in metabolic and nervous system disorders: programmed cell death and molecular signal transduction crosstalk

Maiese

2023

Front. Immunol.

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Life expectancy is increasing throughout the world and coincides with a rise in non-communicable diseases (NCDs), especially for metabolic disease that includes diabetes mellitus (DM) and neurodegenerative disorders. The debilitating effects of metabolic disorders influence the entire body and significantly affect the nervous system impacting greater than one billion people with disability in the peripheral nervous system as well as with cognitive loss, now the seventh leading cause of death worldwide. Metabolic disorders, such as DM, and neurologic disease remain a significant challenge for the treatment and care of individuals since present therapies may limit symptoms but do not halt overall disease progression. These clinical challenges to address the interplay between metabolic and neurodegenerative disorders warrant innovative strategies that can focus upon the underlying mechanisms of aging-related disorders, oxidative stress, cell senescence, and cell death. Programmed cell death pathways that involve autophagy, apoptosis, ferroptosis, and pyroptosis can play a critical role in metabolic and neurodegenerative disorders and oversee processes that include insulin resistance, β-cell function, mitochondrial integrity, reactive oxygen species release, and inflammatory cell activation. The silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), AMP activated protein kinase (AMPK), and Wnt1 inducible signaling pathway protein 1 (WISP1) are novel targets that can oversee programmed cell death pathways tied to β-nicotinamide adenine dinucleotide (NAD+), nicotinamide, apolipoprotein E (APOE), severe acute respiratory syndrome (SARS-CoV-2) exposure with coronavirus disease 2019 (COVID-19), and trophic factors, such as erythropoietin (EPO). The pathways of programmed cell death, SIRT1, AMPK, and WISP1 offer exciting prospects for maintaining metabolic homeostasis and nervous system function that can be compromised during aging-related disorders and lead to cognitive impairment, but these pathways have dual roles in determining the ultimate fate of cells and organ systems that warrant thoughtful insight into complex autofeedback mechanisms.

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mTORC1-Dependent Protein and Parkinson’s Disease: A Mendelian Randomization Study

Cited by 4 publications

References 45 publications

Evaluating the life-extending potential and safety profile of rapamycin: a Mendelian Randomization study of the mTOR pathway

Evaluating the life-extending potential and safety profile of rapamycin: a Mendelian Randomization study of the mTOR pathway

The autophagy proteome in the brain

The impact of aging and oxidative stress in metabolic and nervous system disorders: programmed cell death and molecular signal transduction crosstalk

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