The pathogenesis of Parkinson's disease

The Lancet, Journal Year: 2024, Volume and Issue: 403(10423), P. 293 - 304

Published: Jan. 1, 2024

Language: Английский

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Lysosomal lipid alterations caused by glucocerebrosidase deficiency promote lysosomal dysfunction, chaperone-mediated-autophagy deficiency, and alpha-synuclein pathology

npj Parkinson s Disease, Journal Year: 2022, Volume and Issue: 8(1)

Published: Oct. 6, 2022

Mutations in the GBA gene that encodes lysosomal enzyme β-glucocerebrosidase (GCase) are a major genetic risk factor for Parkinson's disease (PD). In this study, we generated set of differentiated and stable human dopaminergic cell lines express two most prevalent mutations as well knockout vitro modeling system to study relationship between mutant abnormal accumulation α-synuclein. We performed deep analysis consequences triggered by presence protein loss GCase activity different cellular compartments, focusing primarily on compartment, analyzed detail activity, composition, integrity. The generates extensive dysfunction, promoting other enzymes, affecting membrane stability, intralysosomal pH changes, favoring sphingolipids cholesterol. These local events, occurring only at subcellular level, lead an impairment autophagy pathways, particularly chaperone-mediated autophagy, main α-synuclein degradative pathway. findings highlighted role function lipid metabolism PD allowed us describe molecular mechanism understand how can contribute neurotoxic species pathology.

Language: Английский

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The Niemann-Pick type diseases – A synopsis of inborn errors in sphingolipid and cholesterol metabolism

Progress in Lipid Research, Journal Year: 2023, Volume and Issue: 90, P. 101225 - 101225

Published: March 31, 2023

Disturbances of lipid homeostasis in cells provoke human diseases. The elucidation the underlying mechanisms and development efficient therapies represent formidable challenges for biomedical research. Exemplary cases are two rare, autosomal recessive, ultimately fatal lysosomal diseases historically named "Niemann-Pick" honoring physicians, whose pioneering observations led to their discovery. Acid sphingomyelinase deficiency (ASMD) Niemann-Pick type C disease (NPCD) caused by specific variants sphingomyelin phosphodiesterase 1 (SMPD1) NPC intracellular cholesterol transporter (NPC1) or 2 (NPC2) genes that perturb key membrane components, cholesterol, respectively. Patients with severe forms these present visceral neurologic symptoms succumb premature death. This synopsis traces tortuous discovery diseases, highlights important advances respect genetic culprits cellular mechanisms, exposes efforts improve diagnosis explore new therapeutic approaches.

Language: Английский

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Targeting the GBA1 pathway to slow Parkinson disease: Insights into clinical aspects, pathogenic mechanisms and new therapeutic avenues

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 246, P. 108419 - 108419

Published: April 19, 2023

The GBA1 gene encodes the lysosomal enzyme glucocerebrosidase (GCase), which is involved in sphingolipid metabolism. Biallelic variants cause Gaucher disease (GD), a storage disorder characterised by loss of GCase activity and aberrant intracellular accumulation substrates. Carriers have an increased risk developing Parkinson (PD), with odds ratio ranging from 2.2 to 30 according variant severity. do not GD homozygosis can also increase PD risk. Patients carrying show more rapidly progressive phenotype compared non-carriers, emphasising need for modifying treatments targeting pathway. Several mechanisms secondary dysfunction are potentially responsible pathological changes leading PD. Misfolded proteins induce endoplasmic reticulum stress subsequent unfolded protein response impair autophagy-lysosomal This results α-synuclein spread, promotes neurodegenerative changes. Preclinical evidence shows that products promote α-synuclein, however there no convincing substrate GBA1-PD brains. Altered lipid homeostasis could contribute pathology. Treatments target pathway reverse these processes halt/slow progression These range augmentation via therapy, restoration normal trafficking molecular chaperones, reduction therapy. review discusses pathways associated related novel GBA1-targeted interventions treatment.

Language: Английский

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More than meets the eye in Parkinson’s disease and other synucleinopathies: from proteinopathy to lipidopathy

Acta Neuropathologica, Journal Year: 2023, Volume and Issue: 146(3), P. 369 - 385

Published: July 8, 2023

The accumulation of proteinaceous inclusions in the brain is a common feature among neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease (PD), and dementia with Lewy bodies (DLB). main neuropathological hallmark PD DLB are inclusions, known (LBs), enriched not only α-synuclein (aSyn), but also lipid species, organelles, membranes, even nucleic acids. Furthermore, several genetic risk factors for mutations genes involved metabolism, GBA1, VSP35, or PINK1. Thus, it surprising that mechanisms have been implicated PD, inflammation, altered intracellular vesicular trafficking, mitochondrial dysfunction, alterations protein degradation systems, may be directly indirectly connected through homeostasis. In this review, we highlight discuss recent evidence suggests biology important drivers which require renovated attention by neuropathologists. Particularly, address implication lipids aSyn spreading pathology, ER stress. Together, should broaden view proteinopathy lipidopathy.

Language: Английский

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Drug Repurposing of Generic Drugs: Challenges and the Potential Role for Government

Applied Health Economics and Health Policy, Journal Year: 2023, Volume and Issue: 21(6), P. 831 - 840

Published: July 3, 2023

Drug repurposing is the process of identifying a new use for an existing drug or active substance in indication outside scope original indication. has important advantages including reduced development time and costs, potentially large societal healthcare cost savings. However, current generic research faces number challenges obtaining funds. Furthermore, regardless success trial, commercial parties often lack interest pursuing marketing authorisation financial reasons, academic researchers knowledge, funding. Therefore, repurposed does not make it ‘on label’. We propose increase public funding research, funds when trial successful, reduction regulatory burden drugs.

Language: Английский

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A Mouse Model to Test Novel Therapeutics for Parkinson's Disease: an Update on the Thy1-aSyn (“line 61”) Mice

Neurotherapeutics, Journal Year: 2023, Volume and Issue: 20(1), P. 97 - 116

Published: Jan. 1, 2023

Development of neuroprotective therapeutics for Parkinson's disease (PD) is facing a lack translation from pre-clinical to clinical trials. One strategy improvement increase predictive validity studies by using extensively characterized animal models with comprehensive set validated pharmacodynamic readouts. Mice over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter (Thy1-aSyn line 61) reproduce key features sporadic PD, such as progressive loss striatal dopamine, pathology, deficits in motor and non-motor functions, elevation inflammatory markers. Extensive work this model multiple laboratories over past decade further increased confidence its robustness validity, especially analyzing pathomechanisms pathology down-stream pathways, drug testing. Interestingly, while postnatal transgene expression widespread central peripheral neurons, extent progression differs between brain regions, thereby replicating characteristic selective vulnerability neurodegenerative diseases. In-depth characterization these readouts conjunction behavioral has led more informative endpoints Each tested Thy1-aSyn 61 enhances knowledge on how molecular targets, functional are interconnected, optimizing platform towards Here, we present current state art target discovery, validation,

Language: Английский

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Clinical, mechanistic, biomarker, and therapeutic advances in GBA1-associated Parkinson’s disease

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Sept. 12, 2024

Language: Английский

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Neuroinflammation in neuronopathic Gaucher disease: Role of microglia and NK cells, biomarkers, and response to substrate reduction therapy

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Aug. 16, 2022

Background: Neuronopathic Gaucher disease (nGD) is a rare neurodegenerative disorder caused by biallelic mutations in GBA and buildup of glycosphingolipids lysosomes. Neuronal injury cell death are prominent pathological features; however, the role individual types involvement microglia, blood-derived macrophages, immune infiltrates nGD pathophysiology remains enigmatic. Methods: Here, using single-cell resolution mouse brains, lipidomics, newly generated biomarkers, we found induction neuroinflammation pathways involving NK cells, astrocytes, neurons. Results: Targeted rescue Gba microglia neurons, respectively, -deficient, mice reversed glucosylceramide (GlcCer) glucosylsphingosine (GlcSph), concomitant with amelioration neuroinflammation, reduced serum neurofilament light chain (Nf-L), improved survival. Serum GlcSph concentration was correlated Nf-L ApoE models as well GD patients. microglia/macrophage compartment prolonged survival, which further enhanced upon treatment brain-permeant inhibitor synthase, effects mediated via glycosphingolipid homeostasis, reversal activation brain cells. Conclusions: Together, our study delineates cellular deficiency highlighting central driven activation. Brain-permeant small-molecule synthase accumulation bioactive glycosphingolipids, Our findings advance biology whilst identifying compelling biomarkers to improve patient management, enrich clinical trials, illuminate therapeutic targets. Funding: Research grant from Sanofi; other support includes R01NS110354.

Language: Английский

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Who Ever Said It Would Be Easy? Reflecting on Two Clinical Trials Targeting α‐Synuclein

Movement Disorders, Journal Year: 2023, Volume and Issue: 38(3), P. 378 - 384

Published: Jan. 16, 2023

Two recent, high-profile manuscripts reported negative results with two parallel approaches of passive immunization targeting α-synuclein in a population patients early Parkinson's disease (PD). These phase II studies failed to show bona fide disease-modifying neuroprotective effect on PD progression, despite the evidence that these antibodies effectively bind native human serum. Here, we discuss possible reasons could help explain lack clinical efficacy. In particular, highlight (1) wealth supporting notion as valid therapeutic target; (2) target engagement aforementioned studies, especially elusive oligomeric species, likely culprits pathogenesis and/or its propagation; (3) limitations, terms timing immunization, preclinical models, where same succeeded mitigating manifestations; (4) consideration possibly intervening at an even earlier stage future trials; and (5) multitude strategies beyond be used combat α-synuclein-mediated neurodegeneration, if end current approach is not fruitful. Overall, our perception converging developments field, among them novel bioassays biomarkers, improved cellular animal models objective measurements motor activities integrated into trials, further optimized, will gradually move momentum field forward. This, better test concept whether α-synuclein-targeting therapies can indeed deliver "holy grail" neuroprotection benefit community. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC behalf International Parkinson Disorder Society.

Language: Английский

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