Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson’s Disease

Zhu, Zhou; Yang, Chuanbin; Iyaswamy, Ashok; Krishnamoorthi, Senthilkumar; Sreenivasmurthy, Sravan Gopalkrishnashetty; Liu, Jia; Wang, Ziying; Tong, Benjamin Chun‐Kit; Song, Ju‐Xian; Lu, Jiahong; Cheung, King‐Ho; Li, Min

doi:10.3390/ijms20030728

Cited by 185 publications

(146 citation statements)

References 117 publications

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“…Neuroinflammation due to an overactivated and/or chronically activated state of microglia is another source of excessive and uncontrolled release of free radicals. Molecular mechanisms underlying these pathophysiological processes are still under evaluation, but recent evidence comes from studies on high-mobility group box 1 (HMGB1) [11], mammalian target of rapamycin (mTOR) signaling [12], and the nuclear factor, erythroid 2 like 2 (Nrf2) [13], among others. Recent breakthroughs from genetic studies revealed that lysosomal system dysfunction is one of the earliest pathogenetic mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Effect of Alpha-Lipoic Acid in 6-Hydroxydopamine Unilateral Intrastriatal Injected Rats

et al. 2020

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The toxin 6-hydroxydopamine (6-OHDA) is a highly oxidizable dopamine (DA) analog that is widely used for reproducing several cell processes identified in Parkinson’s disease (PD). Due to the close similarity of its neurotoxic mechanism to those of DA, it is suitable as a model for testing the effects of potentially neuroprotective drugs. This study aimed to evaluate the effect of alpha-lipoic acid (LA) on brain oxidative stress (OS) in unilateral intrastriatal (6-OHDA) injected rats. Forty male Wistar rats, four months old (220–260 g), were evaluated. Half of them received LA (35 mg/kg i.p.) from the start to the end of the experiment. On day 2 of the trial, ten LA-supplemented rats and ten non-LA-supplemented rats were subjected to the apomorphine test. Brain homogenates were evaluated for thiobarbituric acid-reactive substances (TBARS) and glutathione peroxidase (GPx) activity. The same evaluation procedures were repeated on day 14 with the remaining animals. An increased TBARS level and decreased GPx activity, suggestive for OS, were recorded in homogenates on day 14 vs. day 2 of the experiment in the 6-OHDA treated rats. The simultaneous application of LA mitigated these changes. Our study demonstrates that the low dose of LA could be of value for decreasing the OS of the neurotoxic 6-OHDA, supporting the need for further studies of the benefit of LA treatment in PD.

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Section: Introductionmentioning

confidence: 99%

Antioxidant Effect of Alpha-Lipoic Acid in 6-Hydroxydopamine Unilateral Intrastriatal Injected Rats

et al. 2020

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“…In PD brains, MTOR expression and AKT functions are impaired [41]. MTOR over-expression impairs autophagy in genetic PD, enhancing α-synuclein deposition [42], and hsa-miR-128-3p down-regulation could be involved in the up-regulation of this pathway.…”

Section: Discussionmentioning

confidence: 99%

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease: A cross-sectional study.

Gámez-Valero

Campdelacreu

Vilas

et al. 2020

Preprint

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Background Dementia with Lewy bodies (DLB) is one of the most common causes of degenerative dementia after Alzheimer’s disease (AD) and presents pathological and clinical overlap with both AD and Parkinson’s disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets have been previously related to neurodegeneration. They contain microRNAs (miRNAs), and their analysis may provide disease biomarkers. Methods Small RNAs from platelets of DLB patients and controls were analyzed by Next Generation Sequencing (NGS), and miRNAs deregulated in DLB were selected. Expression of these miRNAs was then determined and validated by LNA-based qRT-PCR in three consecutive studies from 2017 to 2019 enrolling 162 individuals, including DLB, AD, and PD patients, and healthy controls. Their predictive diagnostic potential was calculated by ROC curve analysis. miRTarbase and miRGate were used for target prediction. Results We profiled the whole platelet miRNA transcriptome from 7 DLB patients and 7 controls using NGS. Twenty-two selected miRNAs were further validated in independent studies (2017–2019) including DLB (n = 59), AD (n = 28), and PD (n = 24) patients, and control individuals (n = 51). Our results demonstrated downregulated expression levels for hsa-let-7d-5p (fold change 0.14; p = 0.006), hsa-miR-132-5p (0.12; p = 0.0015), hsa-miR-142-3p (0.07; p = 0.00047), hsa-miR-146a-5p (0.07; p = 0.00035), hsa-miR-150-5p (0.10; p = 0.0098), hsa-miR-25-3p (0.13; p = 0.0019) and hsa-miR-26b-5p (0.09; p = 0.0014) in DLB compared to AD. ROC curve for this seven-miRNA biosignature yielded an area under the curve (AUC) of 1. Both hsa-miR-142-3p and hsa-miR-150-5p, were down-regulated in DLB compared to controls (AUC = 0.85). Comparing AD and controls, miRNAs hsa-miR-132-5p, hsa-miR-146a-5p, hsa-miR-25-3p, and hsa-miR-6747-3p were up-regulated in AD (AUC = 0.94); and hsa-miR-128-3p and hsa-miR-139-5p were down-regulated in PD compared to controls (AUC = 0.81). Predictive target analysis identified three disease-specific pathway clusters as a result of platelet-miRNA deregulation. In DLB, pathways related to gene expression and small RNA metabolism; in AD, pathways related to stress response and RNA stress granules; and in PD pathways related to protein phosphorylation, metabolism and degradation were identified. Conclusion A platelet-associated bio-signature composed of 7 miRNAs is highly specific and sensitive for distinguishing DLB from AD.

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“…Dysregulated autophagy has been associated with neurodevelopmental disorders, including autism spectrum disorders 9,[35][36][37] , and neurodegenerative diseases such as PD [38][39][40][41] and amyotrophic lateral sclerosis (ALS) 42,43 , where familial cases are associated with mutations in SOD1 44 . Autophagy is crucial to proper axon guidance, vesicular release, dendritic spine architecture, spine pruning, and synaptic plasticity 3,9,37,45,46 .…”

Section: Ros -Induced Increase In Autophagosomes In Kansl1-deficientmentioning

confidence: 99%

KANSL1 Deficiency Causes Neuronal Dysfunction by Oxidative Stress-Induced Autophagy

Linda

Lewerissa

Verboven

et al. 2020

Preprint

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Autophagy is a finely tuned process of programmed degradation and recycling of proteins and cellular components, which is crucial in neuronal function and synaptic integrity. Mounting evidence implicates chromatin remodelling in fine-tuning autophagy pathways. However, this epigenetic regulation is poorly understood in neurons. Here, we investigate the role in autophagy of KANSL1, a member of the nonspecific lethal complex, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation. Loss-of-function of KANSL1 is strongly associated with the neurodevelopmental disorder Koolen-de Vries Syndrome (KdVS).Starting from KANSL1-deficient human induced-pluripotent stem cells, both from KdVS patients and genome-edited lines, we identified superoxide dismutase 1, an antioxidant enzyme, to be significantly decreased, leading to a subsequent increase in oxidative stress and autophagosome accumulation. In KANSL1-deficient neurons, autophagosome accumulation at excitatory synapses resulted in reduced synaptic density, reduced AMPA receptor-mediated transmission and impaired neuronal network activity. Furthermore, we found that increased oxidative stress-mediated autophagosome accumulation leads to increased mTOR activation and decreased lysosome function, further preventing the clearing of autophagosomes. Finally, by pharmacologically reducing oxidative stress, we could rescue the aberrant autophagosome formation as well as synaptic and neuronal network activity in KANSL1-deficient neurons. Our findings thus point towards an important relation between oxidative stress-induced autophagy and synapse function, and demonstrate the importance of H4K16ac-mediated changes in chromatin structure to balance reactive oxygen species- and mTOR-dependent autophagy.

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Balancing mTOR Signaling and Autophagy in the Treatment of Parkinson’s Disease

Cited by 185 publications

References 117 publications

Antioxidant Effect of Alpha-Lipoic Acid in 6-Hydroxydopamine Unilateral Intrastriatal Injected Rats

Antioxidant Effect of Alpha-Lipoic Acid in 6-Hydroxydopamine Unilateral Intrastriatal Injected Rats

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease: A cross-sectional study.

KANSL1 Deficiency Causes Neuronal Dysfunction by Oxidative Stress-Induced Autophagy

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