For over two decades, research conducted by Dr. Lashuel and his group have been pivotal in advancing our understanding of the molecular mechanisms underpinning the pathogenesis of several neurodegenerative diseases, including Parkinson’s, Alzheimer's, Huntington’s, and more recently Amyotrophic Lateral Sclerosis. More specifically, our key contributions include 1) the identification and structural and biochemical characterization of novel intermediates on the amyloid formation pathway; 2) discovering novel therapeutic targets for these diseases; 3) developing novel neuronal models that recapitulate the pathology of Parkinson’s and Huntington’s disease (PD) and methods to image pathology in these models, thus providing powerful platforms for mechanistic studies and drug discovery; 3) pioneering different protein synthetic strategies for site-specific post-translational modifications (PTMs) of proteins, enhancing our ability to elucidate the role of PTMs in neurodegenerative diseases (NDs) and exploiting their potential for developing new therapeutic approaches for the treatment of NDs; 4) creating and validating novel mass spectrometry methods and antibodies that enable accurate detection of aSYN, and capturing the diversity of its sequence and aggregation state in biological samples; 5) Formulating novel hypotheses related to the mechanisms by which protein misfolding and aggregation contribute to neurodegeneration in NDs such as Alzheimer’s disease (AD), PD and Huntington’s disease (HD). To bridge the gap between these scientific discoveries and advancement and clinical applications, we have collaborated with several foundation, biotech, and pharmaceutical companies, including Nestle, Merck, Abbvie, AC Immune, Idorsia, and our own spin-off company, ND BioSciences. The significance of our work is underscored by the substantial interest and support from the Biotech and Pharmaceutical industry, as well as sustained funding from patient-driven foundations, Michael J. Fox Foundation (since 2008-2025 total funding =) and CHDI Foundation frome (2012-2021, total Funding).
Novel model of alpha-synuclein (a-syn) aggregation, toxicity, and Lewy body (LB) formation: Our laboratory has spearheaded efforts to develop novel neuronal and iPSC-based disease models that enable recapitulating the key hallmarks of PD in the human brain, including the development of Lewy pathologies and neurodegeneration. These efforts have led to the development of the first neuronal models that reproduces the different stages of LB formation, from seeding to fibrillization to the formation of LB-like inclusions at the molecular, biochemical, proteomic, transcriptomic, and structural levels. These well-characterized models are now used to 1) investigate the molecular mechanisms underpinning these processes; 2) elucidate their role in a-syn-induced toxicity and potential contributions to the pathogenesis of PD; and 3) screen for therapeutic agents for the treatment of PD based on the modulating the different stages of LB formation and toxic pathways associated with each stage.
Chemical biology of neurodegeneration: During the past 10 years, the Lashuel group has led and pioneered the development of synthetic and semisynthetic strategies that enabled for the first-time site-specific modification at single or multiple sites of several proteins linked to NDs, including a-syn, Tau and several N-terminal fragments of the Huntingtin protein. In addition, my group was the first to develop methods that allow site-specific nitration and made important contributions to the development of methods for site-specific polyubiquitination of proteins (in collaboration with Ashraf Brik). Together, these advances have opened up new possibilities for systematic and comprehensive investigation of the role of PTMs in regulating the structure, function, aggregation, and toxicity of several proteins that play central roles in the pathogenesis of NDs. In addition, the unique synthetic tools and capabilities developed in the Lashuel lab provide, for the first time, opportunities to investigate the cross-talk between different modifications, thus paving the way for deciphering the PTM code of these proteins in health and disease. Our laboratory has worked closely with Foundations such as the Michael J Fox Foundation and CHDI Foundation to scale up the production of many of these reagents and make them available to the PD and HD research communities as standards for biomarker discovery and validation.
The role of post-translational modifications in the pathogenesis of NDs: Research in the Lashuel group has led to the discovery of novel kinases that regulate a-syn (PLK2 and cAbl) and Huntingtin (TBK1 and MST1) phosphorylation, aggregation, clearance, and toxicity. We showed that modulating the activity of these kinases provides a powerful means for lowering protein levels and inhibiting protein aggregation and thus represents a viable therapeutic strategy for the treatment of both PD and HD. These findings highlight the potential role of PTMs in regulating a-syn and Htt clearance and suggest that the enzymes regulating these modifications may constitute viable therapeutic targets for the treatment of PD and HD.
From mechanisms to therapeutic strategies: Research in my group has uncovered novel mechanisms that promote or inhibit pathology formation and spreading, thus providing the basis for novel therapies. For example, recently we showed that specific post-translational modifications such as nitration and glycosylation represent effective novel mechanisms to neutralize the activity of alpha-synuclein aggregates in Parkinson’s disease. We also showed that post-aggregation cleavage of TDP-43 is essential for its seeding activity, suggesting that inhibiting the enzymes that regulate this process represents a novel therapeutic strategy for the treatment of ALS. Finally, we previously demonstrated that fibril growth and seeding capacity are key determinants of amyloid-beta (Eleuteri et al.) and a-syn- (Mahul-Mellier et al.) mediated toxicity and showed that inhibiting fibril growth and seeding capacity using small molecules represents a viable and effective strategy for protecting against neurodegeneration and disease progression in animal and neuronal models of AD and PD, respectively. Finally, we demonstrated that Photobiomodulation (PBM) protects against neuronal loss in a genetic PD model. Further studies are underway to elucidate the mechanisms underlying the beneficial effects of PBM and develop devices to test its efficacy in the clinical setting.
Biomarkers discovery and validation: The Lashuel group is an active and integral member of several international consortia focusing on developing novel biomarkers and assays for early diagnosis, monitoring disease progression, and establishing target engagement in clinical trials of PD. Our role in these consortia ranges from identifying novel biomarkers to developing novel assays and reagents to serving as a reference site for quality control and validation of assays and reagents used by members of the various consortia. Recently, in collaboration with the Dal Perarro and Altug lab at the EPFL, we developed novel biosensors that enable for the first time the detection and reading of complex protein PTMs and quantifying structural biomarkers of proteins associated with neurodegenerative diseases, thus paving the way for novel diagnostics for early disease diagnosis or to monitor disease progression and assess the efficacy of novel therapies.
Thought leadership in the field of neurodegenerative diseases: Prof. Lashuel is recognized as one of the thought leaders in the field of protein misfolding and aggregation in neurodegenerative diseases. His work and expertise are highly sought after as evidenced by his numerous invitations (260) to deliver lectures at prestigious universities and leading conferences/symposiums in the fields of protein aggregation, chemical biology, and neurodegenerative diseases. He is also frequently called upon to participate in writing strategic positioning papers and panels that are charged with defining the research priorities of the field. His role in these capacities is pivotal in building consensus on controversial topics and debates.