Author
Greg M. Pastores
Bio: Greg M. Pastores is an academic researcher from Mater Misericordiae University Hospital. The author has contributed to research in topics: Glymphatic system & Alzheimer's disease. The author has an hindex of 1, co-authored 1 publications receiving 218 citations.
Topics: Glymphatic system, Alzheimer's disease
Papers
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University College Cork1, Columbia University2, ICM Partners3, University of Lyon4, Centre national de la recherche scientifique5, Mater Misericordiae University Hospital6, University of Cambridge7, Nathan Kline Institute for Psychiatric Research8, University College London9, Paris Descartes University10, University of Texas Southwestern Medical Center11, University of Turku12, French Institute of Health and Medical Research13, University of Orléans14
TL;DR: This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs.
Abstract: Neurodegenerative disorders of ageing such as Alzheimer disease, Parkinson disease and Huntington disease are characterized by the presence of neurotoxic misfolded and aggregated proteins. One reason underlying the accumulation of these proteins is insufficient clearance by intracellular and extracellular pathways such as the autophagic–lysosomal network and the glymph system. This article reviews the potential for therapeutically enhancing the clearance of neurotoxic proteins to curtail the onset and slow the progression of neurodegenerative disorders of ageing. Neurodegenerative disorders of ageing (NDAs) such as Alzheimer disease, Parkinson disease, frontotemporal dementia, Huntington disease and amyotrophic lateral sclerosis represent a major socio-economic challenge in view of their high prevalence yet poor treatment. They are often called 'proteinopathies' owing to the presence of misfolded and aggregated proteins that lose their physiological roles and acquire neurotoxic properties. One reason underlying the accumulation and spread of oligomeric forms of neurotoxic proteins is insufficient clearance by the autophagic–lysosomal network. Several other clearance pathways are also compromised in NDAs: chaperone-mediated autophagy, the ubiquitin–proteasome system, extracellular clearance by proteases and extrusion into the circulation via the blood–brain barrier and glymphatic system. This article focuses on emerging mechanisms for promoting the clearance of neurotoxic proteins, a strategy that may curtail the onset and slow the progression of NDAs.
311 citations
Cited by
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Université de Sherbrooke1, Mayo Clinic2, University of Oslo3, University of Düsseldorf4, Kent State University5, Monash University, Clayton campus6, Cornell University7, University of Arizona8, Rhode Island Hospital9, University of Basel10, University of Dundee11, Heidelberg University12, French Institute of Health and Medical Research13, University of Coimbra14, MRC Mitochondrial Biology Unit15, Columbia University Medical Center16, University of Bordeaux17, University of Grenoble18, Johns Hopkins University School of Medicine19, University of Kansas20
TL;DR: The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes.
Abstract: The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes. Accumulating evidence indicates that impaired glucose metabolism in the brain is involved in the cause and progression of neurodegenerative disorders of ageing such as Alzheimer disease. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by rescuing, protecting or normalizing brain energetics.
369 citations
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TL;DR: This Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs in autoimmune disorders and neurodegenerative diseases.
Abstract: Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases - including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease - this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs.
309 citations
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Akershus University Hospital1, University College London2, Discovery Institute3, Northwestern University4, University of Oxford5, National and Kapodistrian University of Athens6, University of Oslo7, Oslo University Hospital8, University of Tromsø9, Foundation for Research & Technology – Hellas10, University of Crete11, University of Cambridge12, Max Planck Society13
TL;DR: A recent review as discussed by the authors examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease, and discusses current preclinical evidence arguing for the use of auto-ophagy modulators as suppressors of age-related pathologies such as neurodegenerative diseases.
Abstract: Autophagy is a fundamental cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development and survival. While autophagy is intimately linked to health, the intricate relationship among autophagy, aging and disease remains unclear. This Review examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease. In addition, we discuss current preclinical evidence arguing for the use of autophagy modulators as suppressors of age-related pathologies such as neurodegenerative diseases. Finally, we highlight key questions and propose novel research avenues that will likely reveal new links between autophagy and the hallmarks of aging. Understanding the precise interplay between autophagy and the risk of age-related pathologies across organisms will eventually facilitate the development of clinical applications that promote long-term health. This Review synthesizes recent research on the mechanisms and roles of autophagy in health, aging and disease and discusses how drugs that modulate the process of autophagy could be used to suppress age-associated diseases.
255 citations
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TL;DR: This work endeavors to define health as a compendium of organizational and dynamic features that maintain physiology, including features of spatial compartmentalization, maintenance of homeostasis over time, and an array of adequate responses to stress.
219 citations
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TL;DR: The authors revealed unique autophagy dysregulation within neurons in five AD mouse models in vivo and identified its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of autophag and pH, multiplex confocal imaging and correlative light electron microscopy.
Abstract: Autophagy is markedly impaired in Alzheimer's disease (AD). Here we reveal unique autophagy dysregulation within neurons in five AD mouse models in vivo and identify its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of autophagy and pH, multiplex confocal imaging and correlative light electron microscopy. Autolysosome acidification declines in neurons well before extracellular amyloid deposition, associated with markedly lowered vATPase activity and build-up of Aβ/APP-βCTF selectively within enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes. This unique pattern, termed PANTHOS (poisonous anthos (flower)), is also present in AD brains. Additional AVs coalesce into peri-nuclear networks of membrane tubules where fibrillar β-amyloid accumulates intraluminally. Lysosomal membrane permeabilization, cathepsin release and lysosomal cell death ensue, accompanied by microglial invasion. Quantitative analyses confirm that individual neurons exhibiting PANTHOS are the principal source of senile plaques in amyloid precursor protein AD models.
157 citations