Rapamycin improves motor function, reduces 4-hydroxynonenal adducted protein in brain, and attenuates synaptic injury in a mouse model of synucleinopathy

Bai, Xiang; Wey, Margaret Chia-Ying; Fernández, Elízabeth; Hart, Matthew J.; Gelfond, Jonathan; Bokov, Alex; Rani, Sheela; Strong, Randy

doi:10.3402/pba.v5.28743

Cited by 52 publications

(46 citation statements)

References 33 publications

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“…We did not find differences in the autophagy markers beclin1 or LC3 following TLR2 activation; however, we did find that TLR2 activation increased the levels of p62/SQSTIM1, a receptor for selective autophagy of target proteins potentially including α-synuclein [22, 42, 45], that is known to increase when autophagy/lysosmal pathways are impaired. Interestingly, activation of autophagy with rapamycin was able to ameliorate the TLR2-mediated increase in α-synuclein, suggesting that activating autophagy can help clear α-synuclein protein, as has been seen before in animal studies [2, 23, 25, 32]. It is also important to note that while our manuscript was in preparation, Kim and colleagues reported similar findings regarding the activation of TLR2 on cell culture neurons and the accumulation of α-synuclein in association with increased p62 [20].…”

Section: Discussionmentioning

confidence: 68%

Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology

et al. 2016

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Inflammation is likely a key contributor to the pathogenesis of Parkinson’s disease (PD), a progressively debilitating neurodegenerative disease that is accompanied by a pathological accumulation of the α-synuclein protein in a staged manner through the brain. What leads to the accumulation of α-synuclein in PD and how this relates to inflammatory pathways, however, is not entirely clear. Toll-like receptor (TLR) signaling is a major pathway mediating inflammation and, in particular, TLR2 is increasingly being implicated in PD. We have, therefore, examined the expression of TLR2 in postmortem brain tissue from PD patients and matched controls. We confirm that TLR2 is increased in PD brain, and find that levels of TLR2 correlate with the accumulation of pathological α-synuclein. TLR2 was expressed on neurons as well as microglia; however, the neuronal rather than glial expression of TLR2 was significantly increased in PD brain in accordance with disease staging, and TLR2 was strongly localized to α-synuclein positive Lewy bodies. In cell culture, activation of neuronal TLR2 induced an inflammatory response, including the secretion of inflammatory cytokines and microglial-activating chemokines, as well as the production of reactive oxygen species. Moreover, activation of neuronal TLR2 increased levels of endogenous α-synuclein protein, which was in turn associated with increased levels of the autophagy/lysosomal pathway marker p62. Finally, promoting autophagy with rapamycin or pharmacological inhibition of the TLR2 signaling pathway prevented the TLR2-mediated increase in α-synuclein in neuronal cell cultures. These results implicate neuronal TLR2 expression in human PD pathogenesis. In particular, the increased expression of TLR2 on neurons may provide new insight into disease pathogenesis and/or options for therapeutic intervention.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1648-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 68%

Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology

et al. 2016

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“…In addition to enhancement of neurotrophic factor/BDNF signaling, IF may counteract PD-related pathogenic processes by stimulating autophagy. Indeed, inhibition of mTOR with rapamycin, which stimulates autophagy, reduced oxidative stress and synaptic damage, and improved motor function in a α-synuclein accumulation-based mouse model of PD (Bai et al, 2015). …”

Section: If and Health Indicators In Laboratory Animalsmentioning

confidence: 99%

Impact of intermittent fasting on health and disease processes

Mattson

Longo

Harvie

2017

Ageing Research Reviews

762

621

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Humans in modern societies typically consume food at least three times daily, while laboratory animals are fed ad libitum. Overconsumption of food with such eating patterns often leads to metabolic morbidities (insulin resistance, excessive accumulation of visceral fat, etc.), particularly when associated with a sedentary lifestyle. Because animals, including humans, evolved in environments where food was relatively scarce, they developed numerous adaptations that enabled them to function at a high level, both physically and cognitively, when in a food-deprived/fasted state. Intermittent fasting (IF) encompasses eating patterns in which individuals go extended time periods (e.g., 16–48h) with little or no energy intake, with intervening periods of normal food intake, on a recurring basis. We use the term periodic fasting (PF) to refer to IF with periods of fasting or fasting mimicking diets lasting from 2 to as many as 21 or more days. In laboratory rats and mice IF and PF have profound beneficial effects on many different indices of health and, importantly, can counteract disease processes and improve functional outcome in experimental models of a wide range of age-related disorders including diabetes, cardiovascular disease, cancers and neurological disorders such as Alzheimer’s disease Parkinson’s disease and stroke. Studies of IF (e.g., 60% energy restriction on 2 days per week or every other day), PF (e.g., a 5 day diet providing 750–1100 kcal) and time-restricted feeding (TRF; limiting the daily period of food intake to 8 h or less) in normal and overweight human subjects have demonstrated efficacy for weight loss and improvements in multiple health indicators including insulin resistance and reductions in risk factors for cardiovascular disease. The cellular and molecular mechanisms by which IF improves health and counteracts disease processes involve activation of adaptive cellular stress response signaling pathways that enhance mitochondrial health, DNA repair and autophagy. PF also promotes stem cell-based regeneration as well as long-lasting metabolic effects. Randomized controlled clinical trials of IF versus PF and isoenergetic continuous energy restriction in human subjects will be required to establish the efficacy of IF in improving general health, and preventing and managing major diseases of aging.

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“…They also suggested a bidirectional process between accumulation of toxic α-synuclein species and GCase levels which may lead to self-propagation of disease (Mazzulli et al, 2011). GBA1 KO mouse embryonic fibroblasts and in-patient derived fibroblasts with GBA1 mutation affects lysosomal recycling resulting in Rab7 accumulation in lysosomes (Magalhaes et al, 2016) while GBA KO in drosophila resulted in abnormal lysosomal pathology, mTOR activity was downregulated and rapamycin ameliorated the lifespan of flies (Bai et al, 2015;Kinghorn et al, 2016). It is important to note that all of the GBA cases that have been examined at post-mortem harbor α-synuclein pathology (Schneider and Alcalay, 2017).…”

Section: Gba (Glucocerebrosidase)mentioning

confidence: 99%

Vesicular Dysfunction and the Pathogenesis of Parkinson’s Disease: Clues From Genetic Studies

Ebanks

Lewis

2020

Front. Neurosci.

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Parkinson's disease (PD) is a common age-related neurodegenerative disorder with disabling motor symptoms and no available disease modifying treatment. The majority of the PD cases are of unknown etiology, with both genetics and environment playing important roles. Over the past 25 years, however, genetic analysis of patients with familial history of Parkinson's and, latterly, genome wide association studies (GWAS) have provided significant advances in our understanding of the causes of the disease. These genetic insights have uncovered pathways that are affected in both genetic and sporadic forms of PD. These pathways involve oxidative stress, abnormal protein homeostasis, mitochondrial dysfunction, and lysosomal defects. In addition, newly identified PD genes and GWAS nominated genes point toward synaptic changes involving vesicles. This review will highlight the genes that contribute PD risk relating to intracellular vesicle trafficking and their functional consequences. There is still much to investigate on this newly identified and converging pathway of vesicular dynamics and PD, which will aid in better understanding and suggest novel therapeutic strategies for PD patients.

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Rapamycin improves motor function, reduces 4-hydroxynonenal adducted protein in brain, and attenuates synaptic injury in a mouse model of synucleinopathy

Cited by 52 publications

References 33 publications

Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology

Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology

Impact of intermittent fasting on health and disease processes

Vesicular Dysfunction and the Pathogenesis of Parkinson’s Disease: Clues From Genetic Studies

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