RESUMO
BACKGROUND: Until recently, about three-quarters of all monogenic Parkinson's disease (PD) studies were performed in European/White ancestry, thereby severely limiting our insights into genotype-phenotype relationships at a global scale. OBJECTIVE: To identify the multi-ancestry spectrum of monogenic PD. METHODS: The first systematic approach to embrace monogenic PD worldwide, The Michael J. Fox Foundation Global Monogenic PD Project, contacted authors of publications reporting individuals carrying pathogenic variants in known PD-causing genes. In contrast, the Global Parkinson's Genetics Program's Monogenic Network took a different approach by targeting PD centers underrepresented or not yet represented in the medical literature. RESULTS: In this article, we describe combining both efforts in a merger project resulting in a global monogenic PD cohort with the buildup of a sustainable infrastructure to identify the multi-ancestry spectrum of monogenic PD and enable studies of factors modifying penetrance and expressivity of monogenic PD. CONCLUSIONS: This effort demonstrates the value of future research based on team science approaches to generate comprehensive and globally relevant results. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
RESUMO
Energy production via the mitochondrial electron transport chain (ETC) and mitophagy are two important processes affected in Parkinson's disease (PD). Interestingly, PINK1, mutations of which cause early-onset PD, plays a key role in both processes, suggesting that these two mechanisms are connected. However, the converging link of both pathways currently remains enigmatic. Recent findings demonstrated that lipid aggregation, along with defective mitochondria, is present in postmortem brains of PD patients. In addition, an increasing body of evidence shows that sphingolipids, including ceramide, are altered in PD, supporting the importance of lipids in the pathophysiology of PD. Here, we identified ceramide to play a crucial role in PINK1-related PD that was previously linked almost exclusively to mitochondrial dysfunction. We found ceramide to accumulate in mitochondria and to negatively affect mitochondrial function, most notably the ETC. Lowering ceramide levels improved mitochondrial phenotypes in pink1-mutant flies and PINK1-deficient patient-derived fibroblasts, showing that the effects of ceramide are evolutionarily conserved. In addition, ceramide accumulation provoked ceramide-induced mitophagy upon PINK1 deficiency. As a result of the ceramide accumulation, ß-oxidation in PINK1 mutants was decreased, which was rescued by lowering ceramide levels. Furthermore, stimulation of ß-oxidation was sufficient to rescue PINK1-deficient phenotypes. In conclusion, we discovered a cellular mechanism resulting from PD-causing loss of PINK1 and found a protective role of ß-oxidation in ETC dysfunction, thus linking lipids and mitochondria in the pathophysiology of PINK1-related PD. Furthermore, our data nominate ß-oxidation and ceramide as therapeutic targets for PD.
Assuntos
Ceramidas/metabolismo , Mitofagia/fisiologia , Doença de Parkinson/fisiopatologia , Proteínas Quinases/deficiência , Animais , Autofagia , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout , Mitofagia/genética , Oxirredução , Oxirredutases/antagonistas & inibidores , Oxirredutases/genética , Doença de Parkinson/genética , Doença de Parkinson/patologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Until recently, about three-quarters of all monogenic Parkinson's disease (PD) studies were performed in European/White ancestry, thereby severely limiting our insights into genotype-phenotype relationships at global scale. The first systematic approach to embrace monogenic PD worldwide, The Michael J. Fox Foundation Global Monogenic PD (MJFF GMPD) Project, contacted authors of publications reporting individuals carrying pathogenic variants in known PD-causing genes. In contrast, the Global Parkinson's Genetics Program's (GP2) Monogenic Network took a different approach by targeting PD centers not yet represented in the medical literature. Here, we describe combining both efforts in a "merger project" resulting in a global monogenic PD cohort with build-up of a sustainable infrastructure to identify the multi-ancestry spectrum of monogenic PD and enable studies of factors modifying penetrance and expression of monogenic PD. This effort demonstrates the value of future research based on team science approaches to generate comprehensive and globally relevant results.
RESUMO
Fatty acid hydroxylase-associated neurodegeneration (FAHN) is a rare disease that exhibits brain modifications and motor dysfunctions in early childhood. The condition is caused by a homozygous or compound heterozygous mutation in fatty acid 2 hydroxylase (FA2H), whose encoded protein synthesizes 2-hydroxysphingolipids and 2-hydroxyglycosphingolipids and is therefore involved in sphingolipid metabolism. A few FAHN model organisms have already been established and give the first insight into symptomatic effects. However, they fail to establish the underlying cellular mechanism of FAHN so far. Drosophila is an excellent model for many neurodegenerative disorders; hence, here, we have characterized and validated the first FAHN Drosophila model. The investigation of loss of dfa2h lines revealed behavioral abnormalities, including motor impairment and flying disability, in addition to a shortened lifespan. Furthermore, alterations in mitochondrial dynamics, and autophagy were identified. Analyses of patient-derived fibroblasts, and rescue experiments with human FA2H, indicated that these defects are evolutionarily conserved. We thus present a FAHN Drosophila model organism that provides new insights into the cellular mechanism of FAHN.
RESUMO
The genus Girardia Ball, 1974 houses freshwater planarian species and is the second after Dugesia Girard, 1850 within Dugesiidae regarding the number of species. It contains 45 species (Tyler et al. 2006-2019) including three recently described: one from China-Girardia sinensis Chen Wang 2015 (Chen et al. 2015), and two cave-dwelling planarians from Brasil-Girardia desiderensis Souza Leal-Zanchet 2016 and Girardia pierremartini Souza Leal-Zanchet 2016 (Souza et al. 2016).
Assuntos
Planárias , Animais , Brasil , China , Europa Oriental , Água DoceRESUMO
At present, the stenostomid genus Myostenostomum Luther, 1960 according to Artois et al. (2013) contains 7 species: M. Bulbocaudatum Luther (type species), M. ilmenicum Rogozin, M. lutheri Rogozin, M. marcusi Rogozin, M. vanderlandi Rogozin, M. fasciatum (Veydovsky) and M. gigerium (Kepner & Carter), although the two latter are thought to belong to the genus Stenostomum Schmidt (Tyler et al. 2006-2015). A remarkable feature of the representatives of the genus Myostenostomum is a muscular ring on their gut.