{"id":10767,"date":"2025-02-18T17:22:35","date_gmt":"2025-02-18T16:22:35","guid":{"rendered":"https:\/\/www.uni.lu\/lcsb-en\/?post_type=news&p=10767"},"modified":"2025-02-18T17:22:37","modified_gmt":"2025-02-18T16:22:37","slug":"miro1-new-kid-on-the-block-in-parkinson-research","status":"publish","type":"news","link":"https:\/\/www.uni.lu\/lcsb-en\/news\/miro1-new-kid-on-the-block-in-parkinson-research\/","title":{"rendered":"Miro1, the new kid on the block in Parkinson\u2019s disease research"},"content":{"rendered":"\n
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Researchers of the Luxembourg Centre for Systems Biomedicine<\/a> (LCSB) keep unfolding the molecular mechanisms underlying neurodegeneration in Parkinson\u2019s disease. In a collaborative effort bringing together different teams, they highlight the impact of a mutation affecting the Miro1 protein. With its link to altered energy metabolism, alpha-synuclein accumulation and loss of dopaminergic neurons, this protein confirms the significant effect of some rare genetic variants and the relevance of mitochondrial pathologies in Parkinson\u2019s disease.<\/p>\n\n\n\n

\nA newcomer in Parkinson\u2019s genetic landscape<\/h4>\n\n\n\n

Complex by nature, Parkinson\u2019s disease is not only clinically but also a genetically heterogenous. If a few well-known mutations are associated with the disease, there is growing evidence that rare variants in different genes might also have substantial effects. RHOT1<\/em> has been identified as one of the genes with the highest burden of rare genetic variants in people with Parkinson\u2019s, meaning alterations in this gene could play an important role in genetic susceptibility to the disease.<\/p>\n\n\n\n

Miro1, a protein encoded by RHOT1<\/em>, has recently been linked to the disease. It is essential for maintaining equilibrium in mitochondria, key components of the human cells, and it interacts with other proteins that are key players in Parkinson\u2019s. In a new study, just published in Brain<\/em><\/a>, LCSB researchers investigated a specific mutation in Miro1 and the role it plays in different cellular activities and pathways relevant for neurodegeneration.<\/p>\n\n\n\n

\u201cAfter describing the first patients carrying distinct mutations in the RHOT1<\/em> gene encoding Miro1 several years ago, we wanted to validate the underlying pathological mechanisms using advanced gene-editing technologies in vitro<\/em> and in vivo<\/em>,\u201d explains Prof. Rejko Kr\u00fcger<\/a>, head of the Translational Neuroscience<\/a> group at the LCSB and co-author of the study.<\/p>\n\n\n\n

\nCombining models for a better overview<\/h4>\n\n\n\n

The scientists performed experiments in patient-derived models in vitro<\/em> and in genetically engineered in vivo<\/em> models. They first used two types of cell cultures derived from pluripotent stem cells, originating either from a patient carrying the Miro1 mutation or healthy controls: Midbrain organoids, 3D cell cultures that mimic a specific region of the human brain, and cultures of dopaminergic neurones.<\/p>\n\n\n\n

\u201cThese patient specific cell culture models allow us to investigate the effects of Miro1 mutations at the cellular level. Particularly brain organoids recapitulate the complexity of the human midbrain and thereby make it possible to study what happens when the Miro1 protein is mutated not only in a single cell but in the complex interaction of various cell types, including dopaminergic neurons and astrocytes,\u201d details Prof. Jens Schwamborn<\/a>, principal investigator of the Developmental & Cellular Biology<\/a> group.

Additionally, to study the effect of the mutation in vivo<\/em>, the researchers developed the first Miro1-mutant mouse model. By introducing a mutation homologous to the one existing in humans with CRISPR\/Cas9 technology, they could observe changes typical of Parkinson\u2019s disease in the brain as well as in the behaviour of mice over time.<\/p>\n\n\n\n

\nConnecting the dots: Mitochondria, calcium signalling and alpha-synuclein<\/h4>\n\n\n\n

Taken together, the results obtained in the organoids, the neuronal cultures and the mice showed that the Miro1 mutation is sufficient to cause the loss of dopaminergic neurons, likely mediated through mitochondrial dysfunction. \u201cThere is increasing evidence that mitochondrial impairment is a major driver of neurodegeneration. The results from the current study further strengthen this finding: The mutation in Miro1 seems to increase susceptibility to mitochondrial damage, which impacts the energy production and ultimately leads to cell death in the investigated models,\u201d underlines Prof. Anne Gr\u00fcnewald<\/a>, head of the Molecular & Functional Neurobiology<\/a> group.

The study goes further, unveiling a novel molecular mechanism linking Miro1 and \u03b1-synuclein accumulation, a hallmark of Parkinson\u2019s disease. The mutation disrupts the regulation of calcium inside the cells, leading to the activation of a protein that cleaves \u03b1-synuclein and promoting its aggregation. This accumulation may in turn exacerbate mutation-dependent mitochondrial damage, resulting in the loss of dopaminergic neurons.<\/p>\n\n\n\n

\nCollaborative work brings significant results<\/h4>\n\n\n\n

Building on the interdisciplinary skills of different teams at the LCSB, together with international partners, has made these results possible. Three LCSB research groups brought their expertise to the table, from the organoid methodology developed by the Developmental & Cellular Biology group to the mitochondria know-how of the Molecular & Functional Neurobiology group and the deep understanding of the genetic basis of Parkinson\u2019s and its validation in patient-derived models of the Translational Neuroscience group. Technical knowledge also played a key part with the contributions of the rodent facility<\/a> and Bioimaging Platform<\/a> for the experimental work with mouse models and image-based analyses.

Pulling these resources together, a strategy at the core of the LCSB, led to significant findings with numerous implications. The study further demonstrates the importance of genetic variance in Parkinson\u2019s disease susceptibility. It provides a new mouse model of Parkinson\u2019s that comprehensively encompass key characteristics of the disease and it identifies Miro1 as a convergent player in neurodegeneration. This protein is now a potential drug target and molecular biomarker, relevant for modelling Parkinson\u2019s disease and developing new disease-modifying therapies.<\/p>\n\n\n\n

—<\/strong>

Scientific publication: <\/strong>Axel Chemla, Giuseppe Arena, Ginevra Sacripanti, Kyriaki Barmpa, Alise Zagare, Pierre Garcia, Vyron Gorgogietas, Paul Antony, Jochen Ohnmacht, Alexandre Baron, Jaqueline Jung, Frida Lind-Holm Mogensen, Alessandro Michelucci, Anne-Marie Marzesco, Manuel Buttini, Thorsten Schmidt, Anne Gr\u00fcnewald, Jens Schwamborn, Rejko Kr\u00fcger & Cl\u00e1udia Saraiva, Parkinson’s disease mutant Miro1 causes mitochondrial dysfunction and dopaminergic neuron loss<\/a>, Brain<\/em>, February 2025.


Top picture by Dr Cl\u00e1udia Saraiva<\/p>\n\n\n

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\nMeet the researchers<\/h2>\n
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    \n \n\"Prof\n <\/figure>\n <\/div>\n
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    Prof Anne GR\u00dcNEWALD<\/h3>\n

    Full professor \/ Chief scientist 1<\/p>\n

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    \n \n\"Prof\n <\/figure>\n <\/div>\n
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    Prof Jens Christian SCHWAMBORN<\/h3>\n

    Full professor in Cellular and Developmental Biology<\/p>\n

    \n \n \n Learn more<\/span>\n <\/span>\n <\/use><\/svg> <\/a>\n<\/div>\n <\/div>\n <\/div>\n<\/div>\n<\/div><\/li>
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    \n \n\"Prof\n <\/figure>\n <\/div>\n
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    Prof Rejko KR\u00dcGER<\/h3>\n

    Full professor in Neurosciences \u2013 FNR PEARL Chair<\/p>\n

    \n \n \n Learn more<\/span>\n <\/span>\n <\/use><\/svg> <\/a>\n<\/div>\n <\/div>\n <\/div>\n<\/div>\n<\/div><\/li><\/ul>\n\n<\/div>\n\n\n\n
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    \nDiscover more<\/h2>\n\n
      \n
    • \n \n \n \n Genetics of Parkinson’s in Luxembourg <\/span>\n <\/use><\/svg> <\/span>\n <\/a>\n<\/li>\n\n\n\n
    • \n \n \n \n Polygenic risk scores for precision medicine <\/span>\n <\/use><\/svg> <\/span>\n <\/a>\n<\/li>\n\n\n\n
    • \n \n \n \n Parkinson’s Research Fund <\/span>\n <\/use><\/svg> <\/span>\n <\/a>\n<\/li>\n<\/ul>\n <\/div>\n<\/section><\/div><\/section>\n","protected":false},"excerpt":{"rendered":"","protected":false},"author":55,"featured_media":10772,"template":"","format":"standard","meta":{"featured_image_focal_point":[],"show_featured_caption":false,"ulux_newsletter_groups":"","uluxPostTitle":"","uluxPrePostTitle":"","_trash_the_other_posts":false,"_price":"","_stock":"","_tribe_ticket_header":"","_tribe_default_ticket_provider":"","_tribe_ticket_capacity":"0","_ticket_start_date":"","_ticket_end_date":"","_tribe_ticket_show_description":"","_tribe_ticket_show_not_going":false,"_tribe_ticket_use_global_stock":"","_tribe_ticket_global_stock_level":"","_global_stock_mode":"","_global_stock_cap":"","_tribe_rsvp_for_event":"","_tribe_ticket_going_count":"","_tribe_ticket_not_going_count":"","_tribe_tickets_list":"[]","_tribe_ticket_has_attendee_info_fields":false},"news-category":[4],"news-topic":[19],"organisation":[340,206,202,215,345,220],"authorship":[55],"acf":[],"yoast_head":"\nMiro1, the new kid on the block in Parkinson\u2019s research - University of Luxembourg I Uni.lu<\/title>\n\n\n\n\n\n\n\n\n\n\n\n\t\n\t\n\t\n\n\n\t\n