Genetics and Pathogenesis of Parkinson's Syndrome

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2022, Номер 18(1), С. 95 - 121

Опубликована: Сен. 13, 2022

Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops virtually unique form of syndrome. Clinical manifestations consist variable motor nonmotor features, myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central peripheral nervous systems, distribution varies pathologies modify PD or trigger similar manifestations. Nearly all influenced. More than 100 genes genetic loci have been identified, cases likely arise from interactions among many common rare variants. Despite its complex architecture, insights experimental dissection coalesce reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms pathogenesis. This emerging understanding syndrome, coupled advances in biomarkers targeted therapies, presages successful precision medicine strategies.

Язык: Английский

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Lysosomal dysfunction in neurodegeneration: emerging concepts and methods

Trends in Neurosciences, Год журнала: 2022, Номер 45(3), С. 184 - 199

Опубликована: Янв. 13, 2022

Язык: Английский

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The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

Frontiers in Aging Neuroscience, Год журнала: 2021, Номер 13

Опубликована: Июль 13, 2021

The elderly population is growing worldwide, with important health and socioeconomic implications. Clinical experimental studies on aging have uncovered numerous changes in the brain, such as decreased neurogenesis, increased synaptic defects, greater metabolic stress, enhanced inflammation. These are associated cognitive decline neurobehavioral deficits. Although not a disease, it significant risk factor for functional worsening, affective impairment, disease exaggeration, dementia, general susceptibility. Conversely, life events related to mental stress trauma can also lead accelerated age-associated disorders dementia. Here, we review human mice rats, those modeling neurodegenerative diseases, that helped elucidate (1) dynamics mechanisms underlying biological pathological of main projecting systems brain (glutamatergic, cholinergic, dopaminergic) (2) effect defective glutamatergic, dopaminergic projection disabilities disorders, Alzheimer’s Parkinson’s diseases. Detailed knowledge age-related diseases be an element development effective ways treatment. In this context, briefly analyze which adverse glutaminergic could targeted by therapeutic strategies developed result our better understanding these damaging mechanisms.

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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Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology

Nature Reviews Molecular Cell Biology, Год журнала: 2023, Номер 25(3), С. 223 - 245

Опубликована: Ноя. 24, 2023

Язык: Английский

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Mitochondria-lysosome contact site dynamics and misregulation in neurodegenerative diseases

Trends in Neurosciences, Год журнала: 2022, Номер 45(4), С. 312 - 322

Опубликована: Март 3, 2022

Язык: Английский

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Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis

Molecular Metabolism, Год журнала: 2022, Номер 60, С. 101481 - 101481

Опубликована: Март 25, 2022

Spatial compartmentalization of metabolic pathways within membrane-separated organelles is key to the ability eukaryotic cells precisely regulate their biochemical functions. Membrane-bound such as mitochondria, endoplasmic reticulum (ER) and lysosomes enable concentration precursors optimized chemical environments, greatly accelerating efficiency both anabolic catabolic reactions, enabling division labor optimal utilization resources. However, also poses a challenge because it creates spatial discontinuities that must be bridged for reaction cascades connected completed. To do so, employ different methods coordinate fluxes occurring in organelles, membrane-localized transporters facilitate regulated metabolite exchange between mitochondria lysosomes, non-vesicular transport via physical contact sites connecting ER with well localized regulatory signaling processes coordinately activity all these organelles.

Язык: Английский

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Mitochondrial signalling and homeostasis: from cell biology to neurological disease

Trends in Neurosciences, Год журнала: 2023, Номер 46(2), С. 137 - 152

Опубликована: Янв. 10, 2023

Efforts to understand how mitochondrial dysfunction contributes neurodegeneration have primarily focussed on the role of mitochondria in neuronal energy metabolism. However, progress understanding etiological nature emerging functions has yielded new ideas about basis neurological disease. Studies aimed at deciphering signal through interorganellar contacts, vesicular trafficking, and metabolic transmission revealed that regulation immunometabolism, cell death, organelle dynamics, neuroimmune interplay are critical determinants neural health. Moreover, homeostatic mechanisms exist protect health turnover via nanoscale proteostasis lysosomal degradation become integrated within signalling pathways support plasticity stress responses nervous system. This review highlights these distinct converge influence contribute disease pathology.

Язык: Английский

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ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling

The Journal of Cell Biology, Год журнала: 2022, Номер 221(7)

Опубликована: Июнь 3, 2022

Mutations in VPS13C cause early-onset, autosomal recessive Parkinson’s disease (PD). We have established that encodes a lipid transfer protein localized to contact sites between the ER and late endosomes/lysosomes. In current study, we demonstrate depleting HeLa cells causes an accumulation of lysosomes with altered profile, including di-22:6-BMP, biomarker PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. addition, DNA-sensing cGAS-STING pathway, which was recently implicated PD pathogenesis, is activated these cells. This activation results from combination elevated mitochondrial DNA cytosol defect degradation STING, lysosome-dependent process. These suggest link ER-lysosome innate immune model human cell line place pathways relevant pathogenesis.

Язык: Английский

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Chiral metal-organic frameworks incorporating nanozymes as neuroinflammation inhibitors for managing Parkinson’s disease

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Дек. 8, 2023

Nanomedicine-based anti-neuroinflammation strategy has become a promising dawn of Parkinson's disease (PD) treatment. However, there are significant gaps in our understanding the therapeutic mechanisms antioxidant nanomedicines concerning pathways traversing blood-brain barrier (BBB) and subsequent inflammation mitigation. Here, we report nanozyme-integrated metal-organic frameworks with excellent activity chiral-dependent BBB transendocytosis as anti-neuroinflammatory agents for treatment PD. These chiral nanozymes synthesized by embedding ultra-small platinum (Ptzymes) into L-chiral D-chiral imidazolate zeolite (Ptzyme@L-ZIF Ptzyme@D-ZIF). Compared to Ptzyme@L-ZIF, Ptzyme@D-ZIF shows higher accumulation brains male PD mouse models due longer plasma residence time more traverse BBB, including clathrin-mediated caveolae-mediated endocytosis. factors contribute superior efficacy reducing behavioral disorders pathological changes. Bioinformatics biochemical analyses suggest that inhibits neuroinflammation-induced apoptosis ferroptosis damaged neurons. The research uncovers biodistribution, metabolic variances, outcomes nanozymes-integrated ZIF platforms, providing possibilities devising anti-PD drugs.

Язык: Английский

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