Conophylline Protects Cells in Cellular Models of Neurodegenerative Diseases by Inducing Mammalian Target of Rapamycin (mTOR)-independent Autophagy

Sasazawa, Yukiko; Sato, Noriaki; Umezawa, Kazuo; Simizu, Siro

doi:10.1074/jbc.m114.606293

Cited by 45 publications

(31 citation statements)

References 32 publications

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“…The growth factor EPO has been shown to protect against dopaminergic neurotoxicity through induction of autophagy and mTOR inhibition . Autophagy also may protect neurons in PD through the maintenance of mitochondrial homeostasis and may not require mTOR inhibition .…”

Section: Mtor and Neurodegenerative Disordersmentioning

confidence: 99%

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

Maiese¹

2015

Brit J Clinical Pharma

161

122

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Neurodegenerative disorders are significantly increasing in incidence as the age of the global population continues to climb with improved life expectancy. At present, more than 30 million individuals throughout the world are impacted by acute and chronic neurodegenerative disorders with limited treatment strategies. The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin, is a 289 kDa serine/threonine protein kinase that offers exciting possibilities for novel treatment strategies for a host of neurodegenerative diseases that include Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy, stroke and trauma. mTOR governs the programmed cell death pathways of apoptosis and autophagy that can determine neuronal stem cell development, precursor cell differentiation, cell senescence, cell survival and ultimate cell fate. Coupled to the cellular biology of mTOR are a number of considerations for the development of novel treatments involving the fine control of mTOR signalling, tumourigenesis, complexity of the apoptosis and autophagy relationship, functional outcome in the nervous system, and the intimately linked pathways of growth factors, phosphoinositide 3‐kinase (PI 3‐K), protein kinase B (Akt), AMP activated protein kinase (AMPK), silent mating type information regulation two homologue one (Saccharomyces cerevisiae) (SIRT1) and others. Effective clinical translation of the cellular signalling mechanisms of mTOR offers provocative avenues for new drug development in the nervous system tempered only by the need to elucidate further the intricacies of the mTOR pathway.

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Section: Mtor and Neurodegenerative Disordersmentioning

confidence: 99%

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

Maiese¹

2015

Brit J Clinical Pharma

161

122

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“…Conophylline is a Vinca alkaloid isolated from the tropical plant Tavertaemontana divaricate and can also be isolated from leaves of Ervatamia microphylla . Conophylline was found to induce autophagy in non‐neuronal and neuronal cell lines in an mTOR‐independent manner (Sasazawa et al , ). By promoting autophagic flux, conophylline promoted the degradation of α‐synuclein aggregates and reduced cell death induced by the neurotoxin MPP + (Sasazawa et al , ).…”

Section: Resultsmentioning

confidence: 99%

Neuroprotective Natural Products for the Treatment of Parkinson's Disease by Targeting the Autophagy-Lysosome Pathway: A Systematic Review

et al. 2017

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The autophagy-lysosome pathway (ALP) is a primary means by which damaged organelles and long-lived proteins are removed from cells and their components recycled. Impairment of the ALP has been found to be linked to the pathogenesis of Parkinson's disease (PD), a chronic neurodegenerative disorder characterized by the accumulation of protein aggregates and loss of dopaminergic neurons in the midbrain. In recent years, some active compounds derived from plants have been found to regulate the ALP and to exert neuroprotective effects in experimental models of PD, raising the possibility that autophagy enhancement may be an effective therapeutic strategy in PD treatment. In this review, we summarize recent findings of natural products that enhance ALP and thereby protect against PD. Research articles were retrieved from PubMed using relevant keywords in combination. Papers related to the topic were identified, and then the reliability of the experiments was assessed in terms of methodology. The results suggest that targeting the ALP with natural products is a promising strategy for PD treatment. However, risk of bias exists in some studies due to the defective methodology. Rigorous experimental design following the guidelines of autophagy assays, molecular target identification and in vivo efficacy evaluation is critical for the development of ALP enhancers for PD treatment in future studies.

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“…This is an AKT/mTOR-independent process, though both AKT and mTOR are activated by IGF1 107 . Additionally, other groups have shown that upregulation of mTOR in HD models increases autophagy and aggregate clearance, rescuing HD-related phenotypes even though mTOR canonically acts as a negative regulator of autophagy by inhibiting ULK1 91,135 . Interestingly, published studies indicate Mn both increases and decreases autophagy in neuronal systems in a biphasic, time-dependent manner 55, 136 .…”

Section: Hd Pathobiologymentioning

confidence: 99%

Manganese and the Insulin-IGF Signaling Network in Huntington’s Disease and Other Neurodegenerative Disorders

Bryan

Bowman

2017

Advances in Neurobiology

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Huntington's disease (HD) is an autosomal dominant neurodegenerative disease resulting in motor impairment and death in patients. Recently, several studies have demonstrated insulin or insulin-like growth factor (IGF) treatment in models of HD, resulting in potent amelioration of HD phenotypes via modulation of the PI3K/AKT/mTOR pathways. Administration of IGF and insulin can rescue microtubule transport, metabolic function, and autophagy defects, resulting in clearance of Huntingtin (HTT) aggregates, restoration of mitochondrial function, amelioration of motor abnormalities, and enhanced survival. Manganese (Mn) is an essential metal to all biological systems but, in excess, can be toxic. Interestingly, several studies have revealed the insulin-mimetic effects of Mn-demonstrating Mn can activate several of the same metabolic kinases and increase peripheral and neuronal insulin and IGF-1 levels in rodent models. Separate studies have shown mouse and human striatal neuroprogenitor cell (NPC) models exhibit a deficit in cellular Mn uptake, indicative of a Mn deficiency. Furthermore, evidence from the literature reveals a striking overlap between cellular consequences of Mn deficiency (i.e., impaired function of Mn-dependent enzymes) and known HD endophenotypes including excitotoxicity, increased reactive oxygen species (ROS) accumulation, and decreased mitochondrial function. Here we review published evidence supporting a hypothesis that (1) the potent effect of IGF or insulin treatment on HD models, (2) the insulin-mimetic effects of Mn, and (3) the newly discovered Mn-dependent perturbations in HD may all be functionally related. Together, this review will present the intriguing possibility that intricate regulatory cross-talk exists between Mn biology and/or toxicology and the insulin/IGF signaling pathways which may be deeply connected to HD pathology and, perhaps, other neurodegenerative diseases (NDDs) and other neuropathological conditions.

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Conophylline Protects Cells in Cellular Models of Neurodegenerative Diseases by Inducing Mammalian Target of Rapamycin (mTOR)-independent Autophagy

Cited by 45 publications

References 32 publications

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

Neuroprotective Natural Products for the Treatment of Parkinson's Disease by Targeting the Autophagy-Lysosome Pathway: A Systematic Review

Manganese and the Insulin-IGF Signaling Network in Huntington’s Disease and Other Neurodegenerative Disorders

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