Research in the Lashuel Laboratory focuses on applying integrated chemical, biophysical, and molecular/cellular biology approaches to uncover the molecular and structural mechanisms that drive protein misfolding, aggregation, pathology formation, and spreading in the brain. By elucidating not only the earliest triggers of pathology formation and neurodegeneration but also the key processes that drive disease progression, the lab aims to lay the foundation for developing mechanism-based, diseasemodifying therapies and next-generation diagnostic tools. Our work spans several neurodegenerative disorders, including Parkinson’s disease (PD), Multiple System Atrophy (MSA), Dementia with Lewy Bodies (DLB), and Alzheimer’s disease, conditions that share common pathological features such as protein misfolding, aggregation, and, in many cases, the accumulation and spread of α-synuclein pathology.

Toward these goals, current research efforts focus on several interconnected themes: 

Molecular Drivers of Disease: Defining the sequence, molecular, and cellular determinants that regulate protein aggregation, toxicity, and pathology spreading in Parkinson’s disease and related synucleinopathies. 

Post-Translational Modifications: Developing new chemical and biochemical methods tools to investigate how specific post-translational modifications (PTMs) or the crosstalk between PTMs influence the structure, function, and dysfunction of α-synuclein and other PD-associated proteins. 

Advanced Stem Cell–Derived Models of Parkinson’s disease: Developing advanced human iPSCderived neuronal systems, mixed-cell cultures, and brain organoids that faithfully recapitulate the complexity and diversity of α-synuclein pathology observed in Parkinson’s disease and related synucleinopathies, including the emergence of co-pathologies. These next-generation models allow us to dissect the dynamic interplay between α-synuclein aggregation, pathology clearance mechanisms, neuroinflammatory responses, and neurodegeneration. They also provide the foundation for an integrated platform to validate therapeutic targets and evaluate diseasemodifying strategies aimed at modulating protein modifications, aggregation, spreading, and clearance.

Biomarkers and Imaging Agents: Identifying biochemical and structural biomarkers, and developing imaging agents, that enable early disease detection, staging, patient stratification, and monitoring of progression and therapeutic response. 

New Imaging Technologies: Collaborating with international partners to develop label-free imaging methods capable of detecting each step along the pathway to pathology formation and maturation, from early oligomerization and fibril formation to the complex cellular processes that generate mature α-synuclein inclusions. 

Through these multidisciplinary and integrative efforts, the Lashuel Lab strives to transform our understanding of neurodegenerative diseases and accelerate the discovery of effective, mechanismbased diagnostics and therapies.