Hilal Lashuel

2012-2013 Visiting Professor, Standford University. Stanford School of Medicine

2011- Associate Professor of Life Sciences-Brain Mind Institute-EPFL

Dir. Laboratory of Chemical Biology of Neurodegeneration

2005-2011 Assistant Professor of Life Sciences-Brain Mind Institute-EPFL

Dir. Laboratory of Molecular Neurobiology and Neuroproteomics

2005-2008 Director- EPFL Proteomic Core Facility

2002-2004 Instructor of Neurology- Harvard Medical School and Brigham and Women's

Hospital

2001-2002 Sabbatical Fellow- Laboratory for Drug Discovery in Neurodegeneration

Harvard Medical School,

2001-2002 Post-doctoral Fellow- Center for Neurologic Diseases

Harvard Medical School and Brigham and Women's Hospital

Advisor- Prof. Peter T. Lansbury

2000-2001 Research Scientist, The Picower Institute for Medical Research, Great Neck

New York

1994-2000 PhD Student; Texas A&M University and the Scripps Research Institute

Advisor- Prof. Jeffery W. Kelly

1990-1994 B.S. City University of New York, Brooklyn College

Dr. Hilal A. Lashuel received his B.Sc. degree in chemistry from the City University of New York in 1994 and completed his doctoral studies at Texas A&M University and the Scripps Research Institute in 2000. After obtaining his doctoral degree, he became a research fellow at the Picower Institute for Medical Research in Long Island New York. In 2001, he moved to Harvard Medical School and the Brigham and Women's Hospital as a research fellow in the Center for Neurologic Diseases and was later promoted to an instructor in neurology at Harvard Medical School. During his tenure (2001-2004) at Harvard Medical School his work focused on understanding the mechanisms of protein misfolding and fibrillogenesis and the role of these processes in the pathogenesis of Parkinson's and Alzheimer's disease. In 2005 Dr. Lashuel moved Switzerland to join the Brain Mind Institute at the Swiss Federal Institute of Technology Lausanne as a tenure-track assistant professor in neurosciences. Currently, Dr. Lashuel is an associate professor of life sciences and the director of the laboratory of molecular and chemical biology of neurodegeneration. (http://lashuel-lab.epfl.ch/).

Research efforts in the Lashuels laboratory focus on understanding the molecular mechanisms of neurodegeneration and developing novel strategies to diagnose and treat neurodegenerative diseases such as Alzheimers and Parkinsons disease. Research in the Lashuel lab is funded by several international funding agencies and foundations, including the Swiss National Science Foundation, European FP7 program (Marie Curie and ERC grants), Human Science Frontiers, Strauss Foundation, Cure the Huntingtons disease foundation and Michael J Fox foundation and is supported by collaborations with pharmaceutical and biotech companies (http://lashuel-lab.epfl.ch/page-50538-en.html), Nestle, Merck-Serono, AC Immune and Johnson and Johnson.

Dr. Lashuels research has resulted in the characterization of novel quaternary structure intermediates on the amyloid pathway, identification of potential therapeutic targets, and new hypotheses concerning the mechanisms of pathogenesis in Alzheimers disease, Parkinsons disease and related disorders. Dr. Lashuel scientific contribution to this field includes i) more than100 publications in major peer reviewed journals including Nature journals, Cell, PNAS, JBC, J. Neuroscience JACS, and Angewandtie Chemie; ii) three patents on novel strategies for preventing protein aggregation and treating autoimmune and inflammatory diseases; iii) more than 150 invited lectures since 2002 and more than 5500 citations (7800 citation-Google Scholar) since 1996. Dr. Lashuel has received several pre-doctoral and post-doctoral awards and fellowships and was the recipient of two prestigious awards given to young investigators; Human Science Frontiers young investigator research award and the European Research Council (ERC) starting independent researcher grant and the ERC proof of concept award (2013) These awards provide more than $2.5 Million to Dr. Lashuel to translate some of his ideas and projects into novel strategies for diagnosing and treating neurodegenerative diseases such as Alzheimers and Parkinsons disease. Dr. Lashuel has chaired and co-organized several international conferences and serves as an academic editor for PLoS ONE, an associate editor for frontiers of molecular neuroscience, member of the Editorial advisory board of ChemBioChem and ad hoc reviewer for several international scientific journals and funding agencies.

Alpha-synuclein as a Potential Biomarker for Parkinson’s Disease and Other Synucleinopathies: Gaps, Challenges, and Opportunities

Hilal Lashuel

Parkinson's disease (PD), the second most common progressive neurodegenerative disease, develops and progresses for 10-15 years before the clinical diagnostic symptoms of the disease are manifested. Furthermore, several aspects of PD pathology overlap with other neurodegenerative diseases (NDDs) linked to alpha-synuclein aggregation, also called synucleinopathies. Therefore, there is an urgent need to discover and validate early diagnostic and prognostic markers that reflect disease pathophysiology, progression, severity, and potential differences in disease mechanisms between PD and other NDDs. The close association between alpha-synuclein (aSyn) and the development of pathology in synucleinopathies, along with the identification of aSyn species in biological fluids, has led to increasing interest in aSyn species as potential biomarkers to detect PD and differentiate it from other synucleinopathies. In this review, we 1) provide an overview of the progress toward mapping the distribution of aSyn species in the brain, peripheral tissues, and biological fluids; 2) present comparative and critical analysis of previous studies to measure total aSyn as well as specific forms of monomeric, modified and aggregated forms of aSyn in different biological fluids; and 3) highlight conceptual and technical gaps and challenges that could hinder the development and validation of reliable aSyn biomarkers and outline a series of recommendations to address these challenges. Finally, we propose a combined biomarker approach based on integrating total aSyn levels with specific biomarkers based on the biochemical features (posttranslational modifications), aggregation and structure of aSyn, in addition to other biomarkers of neurodegeneration. We believe that capturing the diversity of aSyn species is essential to developing robust assays and diagnostics for early detection, patient stratification, monitoring of disease progression, and differentiation between synucleinopathy subtypes. This could transform clinical trial design and implementation, accelerate the development of new therapies, and improve clinical decisions and treatment strategies.

2022

Comparative Analysis of Total Alpha-Synuclein (alpha SYN) Immunoassays Reveals That They Do Not Capture the Diversity of Modified alpha SYN Proteoforms

Lorène Aeschbach, Ritwik Burai, Mohamed Bilal Fares, Layane Hanna-el-Daher, Hilal Lashuel

Background: The development of therapeutics for Parkinson's disease (PD) requires the establishment of biomarker assays to enable stratifying patients, monitoring disease progression, and assessing target engagement. Attempts to develop diagnostic assays based on detecting levels of the alpha-synuclein (alpha SYN) protein, a central player in the pathogenesis of PD, have yielded inconsistent results. Objective: To determine whether the three commercial kits that have been extensively used for total alpha SYN quantification in human biological fluids (from Euroimmun, MSD, and Biolegend) are capable of capturing the diversity and complexity of relevant alpha SYN proteoforms. Methods: We investigated and compared the ability of the different assays to detect the diversity of alpha SYN proteoforms using a library of alpha SYN proteins that comprise the majority of disease-relevant alpha SYN variants and post-translational modifications (PTMs). Results: Our findings showed that none of the three tested immunoassays accurately capture the totality of relevant alpha SYN species, and that these assays are unable to recognize most disease-associated C-terminally truncated variants of alpha SYN. Moreover, several N-terminal truncations and phosphorylationinitration PTMs differentially modify the level of alpha SYN detection and recovery by different immunoassays, and a CSF matrix effect was observed for most of the alpha SYN proteoforms analyzed by the three immunoassays. Conclusion: Our results show that the tested immunoassays do not capture the totality of the relevant alpha SYN species and therefore may not be appropriate tools to provide an accurate measure of total alpha SYN levels in samples containing modified forms of the protein. This highlights the need for next generation alpha SYN immunoassays that capture the diversity of alpha SYN proteoforms.

IOS PRESS2022

Alpha-synuclein as a Potential Biomarker for Parkinson’s Disease and Other Synucleinopathies: Gaps, Challenges, and Opportunities

Hilal Lashuel

2022

Comparative Analysis of Total Alpha-Synuclein (alpha SYN) Immunoassays Reveals That They Do Not Capture the Diversity of Modified alpha SYN Proteoforms

Lorène Aeschbach, Ritwik Burai, Mohamed Bilal Fares, Layane Hanna-el-Daher, Hilal Lashuel

IOS PRESS2022

Alpha-synuclein as a Potential Biomarker for Parkinson’s Disease and Other Synucleinopathies: Gaps, Challenges, and Opportunities

Comparative Analysis of Total Alpha-Synuclein (alpha SYN) Immunoassays Reveals That They Do Not Capture the Diversity of Modified alpha SYN Proteoforms

Identification of key segments of IAPP/aSyn cross-amyloid interactions

Identification of key segments of IAPP/aSyn cross-amyloid interactions

Alpha-synuclein as a Potential Biomarker for Parkinson’s Disease and Other Synucleinopathies: Gaps, Challenges, and Opportunities

Comparative Analysis of Total Alpha-Synuclein (alpha SYN) Immunoassays Reveals That They Do Not Capture the Diversity of Modified alpha SYN Proteoforms