{"id":11307,"date":"2025-04-22T17:25:02","date_gmt":"2025-04-22T15:25:02","guid":{"rendered":"https:\/\/www.uni.lu\/lcsb-en\/?post_type=news&p=11307"},"modified":"2025-04-23T09:33:29","modified_gmt":"2025-04-23T07:33:29","slug":"how-parkinsons-disease-spreads-using-brain-assembloids","status":"publish","type":"news","link":"https:\/\/www.uni.lu\/lcsb-en\/news\/how-parkinsons-disease-spreads-using-brain-assembloids\/","title":{"rendered":"LCSB scientists reveal how Parkinson\u2019s disease spreads using brain assembloids"},"content":{"rendered":"\n
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Parkinson\u2019s disease is a progressive neurodegenerative disease, but how it spreads through the brain remains poorly understood. Now, researchers from the Luxembourg Centre for Systems Biomedicine (LCSB)<\/a> and international collaborators have successfully demonstrated the progressive spread of alpha-synuclein aggregation in a patient-derived assembloid model. Understanding how toxic protein aggregates move between brain regions is crucial to unravelling the mechanisms of early disease progression. The study, published in Advanced Science<\/em><\/a>, provides new insights into this process.<\/p>\n\n\n\n

\nInvestigating the spread of protein aggregates<\/strong><\/h4>\n\n\n\n

While Parkinson\u2019s disease is often associated with symptoms like tremors, stiffness, and slowed movement, the disease actually begins silently, long before these motor symptoms appear. The presence of early, non-motor symptoms has led researchers to investigate how Parkinson\u2019s spreads through the nervous system over time. One leading theory, first proposed by German anatomist Prof. Heiko Braak, suggests that Parkinson\u2019s disease may start in the gut or lower brainstem, before gradually moving upward through the brain in a specific pattern. However, the precise mechanisms driving this spread have remained elusive.<\/p>\n\n\n\n

At the centre of the disease is a protein called alpha-synuclein. In healthy brains, it helps to regulate communication between neurons. In Parkinson\u2019s, this protein misfolds and aggregates, damaging nerve cells and forming abnormal structures known as Lewy bodies – a hallmark of the disease. Understanding how these aggregates propagate between brain regions is critical for developing new treatment strategies. To tackle this challenge, the Developmental & Cellular Biology<\/a> group at the LCSB, led by Prof. Jens Schwamborn, has collaborated with researchers from Eindhoven University of Technology, Universit\u00e4tsklinikum Schleswig-Holstein in L\u00fcbeck, and the Hellenic Pasteur Institute in Athens to recreate the early stages of Parkinson\u2019s disease in the lab using an innovative tool: Brain assembloids.<\/p>\n\n\n\n

\nBrain assembloids: A novel model for disease research<\/strong><\/h4>\n\n\n\n

To investigate Parkinson\u2019s disease progression, the researchers developed assembloids fused from two types of brain organoids. These are miniature, lab-grown brain structures made from human stem cells. One organoid represented the hindbrain, where Parkinson\u2019s disease is thought to begin, and another one represented the midbrain, home to the dopamine-producing neurons that are destroyed in the disease.<\/p>\n\n\n\n

Using induced pluripotent stem cells (iPSCs) derived from Parkinson\u2019s patients with a rare SNCA<\/em> gene triplication, a mutation that causes an overproduction of alpha-synuclein, the team found that hindbrain organoids spontaneously developed toxic protein aggregates. When these were then connected with healthy midbrain organoids to form an assembloid, the alpha-synuclein aggregates began spreading into the healthy midbrain tissue within just 30 days.<\/p>\n\n\n\n

\u201cThis patient-derived assembloid model gives us an unprecedented look at how toxic alpha-synuclein accumulates and spreads between brain regions,\u201d said Prof. Jens Schwamborn<\/a>. \u201cIt is the first time we have been able to observe this pathology progression in a human-based system without overexpressing proteins or relying on artificial triggers.\u201d The study hence provides direct evidence for Braak\u2019s hypothesis, demonstrating that toxic alpha-synuclein aggregates can propagate from one brain region to another.<\/p>\n\n\n\n

\nAlpha-synuclein and its role in Parkinson\u2019s disease progression<\/strong><\/h4>\n\n\n\n

The study showed that the presence of excess alpha-synuclein in the hindbrain was sufficient to trigger its spread to the midbrain, impacting synapses – the vital communication points between neurons. Even before neurons began to die, researchers observed early signs of synaptic dysfunction, a key step in of neurodegeneration.<\/p>\n\n\n\n

\u201cAn increase in alpha-synuclein in the hindbrain alone was sufficient to initiate the spread of pathological alpha-synuclein protein to the healthy midbrain, leading to synaptic dysfunction,\u201d explained Prof. Schwamborn. \u201cThis qualifies the model for future applications to both gain a deeper understanding of the pathology spreading process and develop therapeutic approaches inhibiting this process.\u201c<\/p>\n\n\n\n

The team also used advanced techniques like microelectrode arrays and viral tracing to confirm that the organoids formed functional, directional connections, just like real brain regions. As alpha-synuclein spread, these connections weakened, indicating early disruption of brain network activity.<\/p>\n\n\n\n

\nAdvancing Parkinson\u2019s research: Toward early detection and personalized medicine<\/strong><\/h4>\n\n\n\n

Assembloids provide a controlled environment to study Parkinson\u2019s progression with unprecedented detail. By mimicking the brain\u2019s natural architecture and connectivity, they hold great promise not only for uncovering the earliest events in Parkinson\u2019s disease but also for finding new approaches for precision medicine. As the organoids are derived from individual patients, researchers can study how specific genetic backgrounds affect disease development, and test targeted treatments.<\/p>\n\n\n\n

\u201cThis model offers a unique opportunity to study early disease mechanisms and screen for drugs that could block the spread of alpha-synuclein before irreversible damage occurs,\u201d said Prof. Schwamborn. \u201cUltimately, this could lead to preventive therapies for those at high genetic risk, stopping the disease before it spreads.\u201d<\/p>\n\n\n\n

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Scientific publication:<\/strong> Gomez-Giro G, Frangenberg D, Vega D, Zagare A, Barmpa K, Antony PMA, Robertson G, Sabahi-Kaviani R, Haendler K, Kruse N, Papastefanaki F, Matsas R, Spielman M, Luttge R and Schwamborn JC. <\/strong>Alpha-synuclein pathology spreads in a midbrain-hindbrain assembloid model.<\/a> Advanced Science<\/em>, April 2025.<\/p>\n\n\n\n

Funding:<\/strong> This research was supported by the European Union\u2019s Horizon 2020 Research and Innovation Programme.<\/p>\n\n\n\n

Top image credit: <\/strong>Gemma Gomez-Giro.<\/p>\n\n\n

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\nMeet the researcher<\/h2>\n
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  • \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><\/ul>\n\n<\/div>\n\n<\/div><\/section>\n\n\n
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    \n \n

    \nDiscover more<\/h2>\n\n
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    • \n \n \n \n Miro1 in Parkinson\u2019s disease research <\/span>\n <\/use><\/svg> <\/span>\n <\/a>\n<\/li>\n\n\n\n
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    • \n \n \n \n Parkinson’s Research Fund <\/span>\n <\/use><\/svg> <\/span>\n <\/a>\n<\/li>\n<\/ul>\n <\/div>\n<\/section>","protected":false},"excerpt":{"rendered":"","protected":false},"author":351,"featured_media":11318,"template":"","format":"standard","meta":{"featured_image_focal_point":{"x":0.49,"y":0.49},"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],"authorship":[351],"acf":[],"yoast_head":"\nLCSB scientists reveal Parkinson\u2019s disease spread using brain assembloids- 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