Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases

Cells, Год журнала: 2020, Номер 9(1), С. 150 - 150

Опубликована: Янв. 8, 2020

Mitochondrial dysfunction is a central aspect of aging and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis, Huntington’s disease. Mitochondria are the main cellular energy powerhouses, supplying most ATP by oxidative phosphorylation, which required to fuel essential neuronal functions. Efficient removal aged dysfunctional mitochondria through mitophagy, cargo-selective autophagy, crucial for mitochondrial maintenance health. Mechanistic studies into mitophagy have highlighted an integrated elaborate network that can regulate turnover. In this review, we provide updated overview recent discoveries advancements on pathways discuss molecular mechanisms underlying defects in disease other age-related as well therapeutic potential mitophagy-enhancing strategies combat these disorders.

Язык: Английский

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The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease

Cell Metabolism, Год журнала: 2022, Номер 34(3), С. 396 - 407.e6

Опубликована: Март 1, 2022

We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of riboside (NR), is safe, augments cerebral NAD levels, and impacts metabolism in Parkinson's disease (PD). Thirty newly diagnosed, treatment-naive patients received 1,000 mg NR or placebo for 30 days. treatment was well tolerated led significant, but variable, increase levels-measured by 31phosphorous magnetic resonance spectroscopy-and related metabolites the cerebrospinal fluid. recipients showing increased brain levels exhibited altered metabolism, measured 18fluoro-deoxyglucose positron emission tomography, this associated with mild improvement. augmented metabolome induced transcriptional upregulation processes mitochondrial, lysosomal, proteasomal function blood cells and/or skeletal muscle. Furthermore, decreased inflammatory cytokines serum Our findings nominate as potential neuroprotective therapy PD, warranting further investigation larger trials.

Язык: Английский

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Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure

Journal of Clinical Investigation, Год журнала: 2020, Номер 130(11), С. 6054 - 6063

Опубликована: Авг. 13, 2020

BACKGROUND. While mitochondria play an important role in innate immunity, the relationship between mitochondrial dysfunction and inflammation heart failure (HF) is poorly understood. In this study we aimed to investigate mechanistic link inflammatory activation peripheral blood mononuclear cells (PBMCs), potential antiinflammatory effect of boosting NAD level.

Язык: Английский

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Genetic predispositions of Parkinson’s disease revealed in patient-derived brain cells

npj Parkinson s Disease, Год журнала: 2020, Номер 6(1)

Опубликована: Апрель 24, 2020

Abstract Parkinson’s disease (PD) is the second most prevalent neurological disorder and has been focus of intense investigations to understand its etiology progression, but it still lacks a cure. Modeling diseases central nervous system in vitro with human induced pluripotent stem cells (hiPSC) infancy potential expedite discovery validation new treatments. Here, we discuss interplay between genetic predispositions midbrain neuronal impairments people living PD. We first summarize prevalence causal genes risk factors reported 74 epidemiological genomic studies. then present meta-analysis 385 hiPSC-derived lines from 67 recent independent original research articles, which point towards specific neurons patients, within context predispositions. Despite heterogeneous nature disease, current iPSC models reveal converging molecular pathways underlying neurodegeneration range familial sporadic forms disease. Altogether, consolidating our understanding robust cellular phenotypes across cohorts patients may guide future personalized drug screens preclinical research.

Язык: Английский

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NAD ⁺ homeostasis in human health and disease

EMBO Molecular Medicine, Год журнала: 2021, Номер 13(7)

Опубликована: Май 27, 2021

Язык: Английский

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Dysregulation of mitochondria-lysosome contacts by GBA1 dysfunction in dopaminergic neuronal models of Parkinson’s disease

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Март 22, 2021

Abstract Mitochondria-lysosome contacts are recently identified sites for mediating crosstalk between both organelles, but their role in normal and diseased human neurons remains unknown. In this study, we demonstrate that mitochondria-lysosome can dynamically form the soma, axons, dendrites of neurons, allowing bidirectional crosstalk. Parkinson’s disease patient derived harboring mutant GBA1 exhibited prolonged due to defective modulation untethering protein TBC1D15, which mediates Rab7 GTP hydrolysis contact untethering. This dysregulation was decreased (β-glucocerebrosidase (GCase)) lysosomal enzyme activity could be rescued by increasing with a GCase modulator. These defects resulted disrupted mitochondrial distribution function, further TBC1D15 -linked neurons. Together, our work demonstrates potential as an upstream regulator function dynamics midbrain dopaminergic disease.

Язык: Английский

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Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction

Redox Biology, Год журнала: 2021, Номер 43, С. 101988 - 101988

Опубликована: Апрель 24, 2021

Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma common neurodegenerative disease in which levels of NAD decline. We assess the effects nicotinamide (a precursor to NAD) on retinal ganglion cells (the affected neuron glaucoma) normal physiological conditions across range glaucoma relevant insults including mitochondrial stress axon degenerative insults. demonstrate cell somal, axonal, dendritic neuroprotection by rodent models represent isolated ocular hypertensive, degenerative, performed metabolomics enriched small molecular weight metabolites retina, optic nerve, superior colliculus demonstrates that hypertension induces widespread metabolic disruption, consistent changes α-ketoglutaric acid, creatine/creatinine, homocysteine, glycerophosphocholine. This disruption prevented nicotinamide. provides further neuroprotective increasing oxidative phosphorylation, buffering preventing stress, size motility whilst simultaneously dampening action potential firing frequency. These data support continued determination utility long-term treatment as therapy human glaucoma.

Язык: Английский

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GBA Variants and Parkinson Disease: Mechanisms and Treatments

Cells, Год журнала: 2022, Номер 11(8), С. 1261 - 1261

Опубликована: Апрель 8, 2022

The GBA gene encodes for the lysosomal enzyme glucocerebrosidase (GCase), which maintains glycosphingolipid homeostasis. Approximately 5–15% of PD patients have mutations in gene, making it numerically most important genetic risk factor Parkinson disease (PD). Clinically, GBA-associated is identical to sporadic PD, aside from earlier age at onset (AAO), more frequent cognitive impairment and rapid progression. Mutations can be associated with loss- gain-of-function mechanisms. A key hallmark presence intraneuronal proteinaceous inclusions named Lewy bodies, are made up primarily alpha-synuclein. may lead loss GCase activity dysfunction, impair alpha-synuclein metabolism. Models deficiency demonstrate dysfunction autophagic-lysosomal pathway subsequent accumulation This also aberrant lipid metabolism, including glycosphingolipids, glucosylceramide glucosylsphingosine. Certain cause misfolded retained endoplasmic reticulum (ER), activating stress responses unfolded protein response (UPR), contribute neurodegeneration. In addition these mechanisms, a has been mitochondrial neuroinflammation, implicated pathogenesis PD. review discusses pathways GBA-PD highlights potential treatments act target prevent

Язык: Английский

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Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease, and Parkinson’s disease, Huntington’s disease and Amyotrophic Lateral Sclerosis -An updated review

Mitochondrion, Год журнала: 2023, Номер 71, С. 83 - 92

Опубликована: Июнь 1, 2023

Язык: Английский

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Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Ноя. 11, 2023

Abstract Mitochondrial dysfunction is strongly implicated in the etiology of idiopathic and genetic Parkinson’s disease (PD). However, strategies aimed at ameliorating mitochondrial dysfunction, including antioxidants, antidiabetic drugs, iron chelators, have failed disease-modification clinical trials. In this review, we summarize cellular determinants impairment electron transport chain complex 1, increased oxidative stress, disturbed quality control mechanisms, bioenergetic deficiency. addition, outline pathways to neurodegeneration current context PD pathogenesis, review past treatment an attempt better understand why translational efforts thus far been unsuccessful.

Язык: Английский

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