Major cross-functional project Deep Brain Stimulation (DBS)

Our objectives: 

• Aim 1 - Candidate gene identification and functional screening in simple organisms
• Aim 2 - Using complex organoid systems to model circuits and probe PD mutations
• Aim 3 - Map motor circuitry downstream of dopaminergic signaling for stimulation

Motor defects in Parkinson's disease (PD) are associated with the degeneration of dopaminergic neurons in the substantia nigra, which impairs the recruitment of the mesencephalic locomotor region — a complex structure conserved across vertebrates that plays a key role in controlling movement. While classical studies of the disease tend to focus on a single scale, whether molecular, cellular, physiological or cognitive, understanding how genetic mutations associated with PD result in diverse motor and cognitive defects requires approaches that span multiple scales, disciplines and disease models. Current therapies, including deep brain stimulation (DBS), remain limited in their ability to address the full complexity of the disease. To overcome these challenges, the Paris Brain Institute has launched the "(Beyond) DBS" initiative, a multidisciplinary and collaborative program aimed at developing novel DBS strategies targeting resilient motor circuits in PD, with the ultimate goal of bridging fundamental research and innovative therapeutic approaches for patients.

The project entitled " From genetic mutations to motor circuit dysfunctions and recovery" (previously DBS) is structured around three complementary aims. 

• Aim 1 focuses on identifying and validating candidate genes linked to PD through large genetic datasets and screening in simple model organisms, followed by CRISPR/Cas9-based validation in iPSC lines.
• Aim 2 leverages iPSC-derived brain organoids and assembloids to explore the impact of PD-associated mutations on molecular signatures, cellular pathways, and the organization of relevant neural circuits.
• Aim 3 investigates the neuronal circuits underlying motor initiation in both healthy and PD conditions, with the goal of identifying brainstem motor circuits whose stimulation could restore locomotor and postural functions in patients. 

These aims are further supported by interdisciplinary Collective Interest Projects fostering collaboration across the institute. Together, this research provides new insights into the molecular and network mechanisms driving motor dysfunction in PD, paving the way for circuit-specific interventions, and personalized therapeutic strategies.

The DBS initiative carries several interconnected ambitions:

• Identify new genes associated with Parkinson’s disease and validate them through large genetic datasets and functional screening across multiple model organisms, to expand our understanding of the genetic architecture of the disease
• Decipher the molecular and network mechanisms leading to motor, cognitive and affective dysfunctions in PD patients, by identifying new disease-causing genes and characterizing the biological pathways they disrupt
• Map the resilient motor circuits of the brainstem that remain intact in PD patients and could be targeted for therapeutic intervention
• Bridge the gap between fundamental discoveries and clinical applications by combining genetic, cellular and circuit-level approaches across multiple species and models

Conceive how to develop in the future personalized therapeutic strategies  by targeting intact command neurons through pharmacology or next-generation deep brain stimulation approaches combined with optogenetics or sonogenetics. These ambitions will be possible through the combination of complementary expertise to observe and integrate findings across models, timescales, and brain regions, fostering interdisciplinary collaboration and open scientific communication within and beyond the institute. 

Furthermore, the Collective Interest Projects (CIPs) were designed to bring together researchers from different scientific backgrounds around a shared question that spans multiple fields. By pairing complementary expertise, these projects foster genuine interdisciplinary collaboration and encourage new ways of thinking about Parkinson's disease, from genes to circuits and from model organisms to patients, leveraging new methods such as optogenetics or ultrasound stimulation.

The initiative “From genetic mutations to motor circuit dysfunctions and recovery” has already generated significant advances across its three research axes. 

In the field of genetics, the project has led to the identification of hundreds of candidate genes associated with early-onset Parkinsonism, several of which have been successfully validated, confirming the strong discovery power of this approach. Functional screening pipelines in simple model organisms have also been established, enabling rapid and effective assessment of newly identified PD genes and providing insights into the biological pathways they affect. 

At the cellular level, the use of chimeric brain organoid models carrying known and newly identified PD-associated mutations has allowed a comparative and robust analysis of the molecular and cellular defects caused by these mutations. In parallel, assembloid models combining cortical, striatal, and midbrain components are being used to investigate how specific PD mutations affect both brain development and neuronal activity over time. 

Regarding motor circuit investigations, the project is advancing our understanding of the brainstem circuits controlling locomotion and posture, revealing conserved molecular markers across species that could guide more precise stimulation strategies in PD patients. Finally, new analytical tools based on whole-body movement coordination have been developed, showing that preoperative motor patterns can predict postoperative treatment outcomes, opening promising perspectives for personalized medicine in PD.

On a broader scale, an international conference was organized in early 2026, bringing together leading experts from around the world to share their latest work with the DBS consortium and the wider institute community: “Innovations for Parkinson’s Disease”. This scientific gathering was a unique opportunity to stimulate discussion, exchange perspectives and explore emerging innovations in the field of Parkinson's disease research and treatment, combining both results from the lab and from the industry.

Aim 1 – Publications 

• The genetics of autosomal recessive early-onset Parkinson's disease. Cogan G, Lesage S, Brice A. Curr Opin Neurobiol. 2025 Dec;95:103141. doi: 10.1016/j.conb.2025.103141. PMID: 41253044.
• Should ITSN1 be considered as a Mendelian Parkinson's disease gene? Description of three novel families. Cogan G, Tesson C, Welment L, Clot F, LeGuern E, Lanore A, Dürr A, Cormier-Dequaire F, Debilly B, Planes M, Mangone G, Lesage S, Brice A. NPJ Parkinsons Dis. 2025 Oct 17;11(1):295. doi: 10.1038/s41531-025-01141-6. PMID: 41107259.