Neurotoxic reactive astrocytes induce cell death via saturated lipids

Nature, Journal Year: 2021, Volume and Issue: 599(7883), P. 102 - 107

Published: Oct. 6, 2021

Language: Английский

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Lipid droplet biogenesis and functions in health and disease

Nature Reviews Endocrinology, Journal Year: 2023, Volume and Issue: 19(8), P. 443 - 459

Published: May 23, 2023

Language: Английский

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APOE4 disrupts intracellular lipid homeostasis in human iPSC-derived glia

Science Translational Medicine, Journal Year: 2021, Volume and Issue: 13(583)

Published: March 3, 2021

The

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Neuropathology and molecular diagnosis of Synucleinopathies

Molecular Neurodegeneration, Journal Year: 2021, Volume and Issue: 16(1)

Published: Dec. 18, 2021

Synucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons glia, the form Lewy bodies, neurites, neuronal cytoplasmic inclusions, glial inclusions. can be divided into two major disease entities: body multiple system atrophy (MSA). Common clinical presentations Parkinson's (PD), PD with dementia, dementia bodies (DLB), while MSA has subtypes, predominant cerebellar ataxia parkinsonism. There currently no disease-modifying therapies for synucleinopathies, but information obtained from molecular genetics models that explore mechanisms conversion to oligomers insoluble fibrils offer hope eventual therapies. It remains unclear how associated distinct cellular pathologies (e.g., inclusions) what factors determine neuroanatomical cell type vulnerability. Accumulating evidence vitro vivo experiments suggests species derived "strains" having different seeding properties. Recent advancements assays, such as real-time quaking-induced (RT-QuIC) protein misfolding cyclic amplification (PMCA), not only demonstrate activity also exciting opportunities diagnosis using readily accessible peripheral tissue samples. Cryogenic electron microscopy (cryo-EM) structural studies recombinant or brain-derived filaments provide new insight synucleinopathies. In this review, we describe clinical, genetic neuropathologic features including a discussion evolution classification staging disease. We brief on proposed formation, well supporting existence strains MSA.

Language: Английский

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Initiation and propagation of α-synuclein aggregation in the nervous system

Molecular Neurodegeneration, Journal Year: 2020, Volume and Issue: 15(1)

Published: March 6, 2020

The two main pathological hallmarks of Parkinson's disease are loss dopamine neurons in the substantia nigra pars compacta and proteinaceous amyloid fibrils composed mostly α-synuclein, called Lewy pathology. Levodopa to enhance dopaminergic transmission remains one most effective treatment for alleviating motor symptoms (Olanow, Mov Disord 34:812-815, 2019). In addition, deep brain stimulation (Bronstein et al., Arch Neurol 68:165, 2011) modulate basal ganglia circuit activity successfully alleviates some symptoms. MRI guided focused ultrasound subthalamic nucleus is a promising therapeutic strategy as well (Martinez-Fernandez Lancet 17:54-63, 2018). However, date, there exists no that stops progression this disease. findings α-synuclein can be released from inherited through interconnected neural networks opened door discovering novel strategies prevent formation spread pathology with goal halting PD its tracks. This hypothesis based on discoveries pathologic aggregates induce endogenous protein adopt similar conformation, thus self-propagating. Phase I clinical trials currently ongoing test treatments such immunotherapy neuron extracellular aggregates. Although tremendous progress has been made understanding how forms spreads throughout brain, cell intrinsic factors also play critical role mechanisms increase levels, selective expression profiles distinct subtypes, mutations altered function proteins involved synthesis degradation, oxidative stress. Strategies should consider release propagation, mechanisms.

Language: Английский

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Lipid Droplets in Neurodegenerative Disorders

Frontiers in Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: July 29, 2020

Lipid droplets have been long regarded as simple storage depots of intracellular neutral lipid. However, recent studies informed significant roles for lipid in cellular signaling, metabolic disease, pathophysiology, and inflammation. While droplet biology has well-explored the periphery, within brain are relatively understudied. The presence function these dynamic organelles central nervous system recently gained much more attention, especially context neurodegeneration. In this review, we seek to summarize current understanding brain, with an emphasis on their relevance neurodegenerative diseases. We hope update investigators effort open new avenues investigation into under-appreciated organelle.

Language: Английский

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Parkinson’s disease: proteinopathy or lipidopathy?

npj Parkinson s Disease, Journal Year: 2020, Volume and Issue: 6(1)

Published: Jan. 3, 2020

Abstract Lipids play a more significant role in Parkinson’s disease and its related brain disorders than is currently recognized, supporting “lipid cascade”. The 14 kDa protein α-synuclein (αS) strongly associated with (PD), dementia Lewy bodies (DLB), other synucleinopathies such as multiple system atrophy, even certain forms of Alzheimer’s disease. Rigorously deciphering the biochemistry αS native systems key to developing treatments. highly expressed brain, second most lipid-rich organ, has been proposed be lipid-binding that physiologically interacts phospholipids fatty acids (FAs). αS-rich cytoplasmic inclusions called neurites are hallmark lesions synucleinopathies. Excess αS–membrane interactions may trigger proteinaceous aggregation by stimulating primary nucleation. However, also exert toxicity prior or independent self-aggregation, e.g., via excessive membrane interactions, which promoted lipids FAs. A complex αS-lipid landscape exists, comprises both physiological pathological states αS. As novel insights about composition occur, new lipid-related PD drug candidates emerge, genome-wide association studies (GWAS) increasingly validate hits lipid-associated pathways, it seems timely review our current knowledge consider roles for these pathways

Language: Английский

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Tumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence

Redox Biology, Journal Year: 2021, Volume and Issue: 43, P. 102006 - 102006

Published: May 14, 2021

Tumor recurrence is a major clinical issue that represents the principal cause of cancer-related deaths, with few targetable common pathways. Mechanisms by which residual tumors persist and progress under continuous shift between hypoxia-reoxygenation after neoadjuvent-therapy are unknown. In this study, we investigated role lipid metabolism tumor redox balance in recurrence. Lipidomics, proteomics mass spectrometry imaging approaches where applied to mouse models Genetic pharmacological inhibitions mediators were used vivo functional assays vitro. We found stearoyl-CoA desaturase-1 (SCD1) expressed cancer cells fatty acid binding protein-4 (FABP4) produced endothelial (TECs) adipocytes microenvironment (TME) essential for relapse response tyrosine kinase inhibitors (TKI) chemotherapy. SCD1 FABP4 also upregulated recurrent human breast samples correlated worse prognosis patients different types tumors. Mechanistically, leads (FA) desaturation derived from TEM enhances droplet (LD) cells, cooperatively protect oxidative stress-induced ferroptosis. revealed mobilization elicit intrinsic antioxidant anti-ferroptotic resources survival regrowth harsh TME. Inhibition transport TME inhibitor reduced genetic — or targeting vivo, was abolished completely. This finding unveils it worth taking advantage addiction, as vulnerability design novel treatment strategy prevent

Language: Английский

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Lipid droplets in the nervous system

The Journal of Cell Biology, Journal Year: 2021, Volume and Issue: 220(7)

Published: June 21, 2021

Lipid droplets are dynamic intracellular lipid storage organelles that respond to the physiological state of cells. In addition controlling cell metabolism, they play a protective role for many cellular stressors, including oxidative stress. Despite prior descriptions appearing in brain as early century ago, only recently has cells found begun be understood. droplet functions have now been described nervous system context development, aging, and an increasing number neuropathologies. Here, we review basic mechanisms formation, turnover, function discuss how these enable different types under healthy pathological conditions.

Language: Английский

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Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration

Nature Metabolism, Journal Year: 2023, Volume and Issue: 5(3), P. 445 - 465

Published: March 23, 2023

Language: Английский

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