Dario Alessi: Rabs and LRRK2 at the Crossroads of Organelle Stress and Parkinson’s Disease

FELDBERG PRIZE LECTURE at FMP Berlin

The Feldberg Foundation promotes scientific contact between German and English scientists within the sphere of experimental medical research, primarily by the establishment of scientific exchange lectures. Each year a German and a British scientist are chosen to receive a prize.

DARIO ALESSI (University of Dundee)
“Rabs and LRRK2 at the Crossroads of Organelle Stress and Parkinson’s Disease”

Short CV

Address
MRC Protein Phosphorylation and Ubiquitylation Unit
School of Life Sciences
University of Dundee
Dow Street
Dundee DD15EH
United Kingdom
Email:d.r.alessi@dundee.ac.uk
Phone: +44 1382 385602
Website: https://www.ppu.mrc.ac.uk/research/principal-investigator/dario-alessi

Education
University of Birmingham
1985-1988 BSc: Biochemistry with Biotechnology (awarded the Perry Prize)
1988-1991 PhD: Synthesis of a new type of spin-labelled nucleotide and its use in biology. Supervisors: Prof. Ian Trayer and Dr David Trentham FRS. PhD Studentship supported by a Wellcome Trust Prize Studentship

Appointments
1991-1996 MRC Postdoctoral Fellowship in the laboratory of Professor Sir Philip Cohen FRS, MRC Protein Phosphorylation Unit, University of Dundee
1997-Present Principal Investigator, MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee
2012-Present Director, MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee
Honors and Awards
1999 Colworth Medal of the British Biochemical Society
2000 The Eppendorf Young European Investigator Award
2002 Elected a Fellow of the Royal Society of Edinburgh
2002 Morgagni Young Investigator Prize (Padova, Italy)
2002 Pfizer Academic Award for Europe
2002 Royal Society of Edinburgh Makdougall Brisbane Prize
2002 Philip Leverhulme Prize
2003 FEBS Anniversary Prize Gesellschaft für Biochemie und Molekular Biologie
2004 The RD Lawrence Lecture of Diabetes UK
2005 Elected a Member of EMBO
2005 EMBO Gold Medal awarded annually to a young European scientist
2006 The Francis Crick Prize Lecture of the Royal Society
2008 Elected a Fellow of The Royal Society
2012 Elected to the Academy of Medical Sciences
2014 Sackler Lecture of the Academy of Medical Sciences
2018 Michael J Fox Foundation Langston Award for research on Parkinson’s disease
2023 Ed Krebs Lecture, University of Seattle
2023 Louis Jeantet-Collen Prize for Translational Medicine
2023 Order of the British Empire King's Birthday Honours List
2023 Michael J Fox Foundation Robert A Pritzker prize for Leadership in Parkinson’s Research
2026 Feldberg Foundation Prize

Current Professional and Advisory Roles
1. Lead of the Michael J. Fox Foundation LRRK2 Investigative Therapeutics Exchange (LITE) initiative, a $40+ million international translational programme focused on bridging fundamental discoveries in the LRRK2 pathway with industry-led drug development for Parkinson’s disease.
2. President, International Union of Biochemistry and Molecular Biology (IUBMB) (2024–2027).
3. Associate Member, UK Dementia Research Institute (2019–present).
4. Advisory Editorial Board Member for EMBO Molecular Medicine, The EMBO Journal, and EMBO Reports (2010–present), and Journal of Cell Science (2008–present).
5. Scientific Advisory Board Member, Vincere Biosciences Inc. (2019–present).
6. Jury Member, BBVA Foundation Frontiers of Knowledge Award, Madrid (2009–present), and Louis Jeantet Prize for Medicine (2023–present).
Collaboration and Open Science
Alessi has a strong track record of fostering international collaborations and promoting open science. This includes major collaborative initiatives in Parkinson’s disease research with the Michael J. Fox Foundation and the Aligning Science Across Parkinson’s (ASAP) program, as well as participation in the UK Dementia Research Institute. He also contributes broadly to research on protein phosphorylation and ubiquitylation through his leadership of the MRC Protein Phosphorylation and Ubiquitylation Unit (PPU), and by supporting pharmaceutical companies through the Division of Signal Transduction Therapy Unit (DSTT), a longstanding and unique collaboration between academia and industry. Through the Michael J. Fox Foundation LRRK2 Investigative Therapeutics Exchange (LITE) program, Alessi currently supports the research efforts of more than 20 therapeutic companies working to develop new treatments targeting the LRRK2 pathway in Parkinson’s disease.
To support the global research community, Alessi actively promotes sustainable science practices by freely sharing reagents, services, datasets, and experimental protocols through dedicated online platforms including mrcppureagents.dundee.ac.uk, lrrk2.bio, and protocols.io. He has also contributed to a UK “National Asset” initiative, designed to make tools, datasets, and technologies generated by MRC Units and Institutes broadly accessible via a centralized resource database (resources.mrc.ukri.org).
Through these efforts, Alessi promotes a culture of openness and collaboration, facilitates reproducibility, and accelerates scientific progress by ensuring that high-quality research tools, data, and knowledge are widely available to the global biomedical research community.
Mentorship
Alessi has personally supervised and trained 30 PhD students and more than 40 postdoctoral researchers, the majority of whom have progressed to leadership positions in academia, industry, and biotechnology. Through his leadership of the MRC Protein Phosphorylation and Ubiquitylation Unit and the Division of Signal Transduction Therapy Unit, he has also created an exceptional training environment that has provided many additional graduate students, postdoctoral fellows, and visiting scientists with unique opportunities to develop their careers.
These programmes offer trainees exposure not only to cutting-edge fundamental research but also to highly collaborative and translational science, including partnerships with pharmaceutical companies and international research consortia. Through this mentoring and training framework, Alessi has helped cultivate a new generation of scientists equipped to bridge basic discovery with therapeutic innovation.

Published papers and reviews
Dario Alessi’s publications have accumulated > 109,000 citations h-index is 160.
17 research papers and 5 reviews have been cited >1000 times https://scholar.google.co.uk/citations?user=9gPyVfsAAAAJ&hl=en.

Abstract

Parkinson’s disease is increasingly recognised as a disorder of endolysosomal stress, in which failures of the systems that maintain healthy membranes, vesicles and lysosomes contribute to neuronal dysfunction. A central player in this process is LRRK2, a protein kinase whose hyperactivation is a common cause of inherited Parkinson’s disease and a major focus of ongoing clinical trials. Our work has revealed an unexpected two-way relationship between LRRK2 and Rab GTPases, the master regulators of membrane homeostasis and trafficking. Rabs are not simply substrates phosphorylated by LRRK2: a specialised group of “recruiter Rabs” directs LRRK2 to stressed organelles and vesicles, positioning the kinase at membranes where it becomes activated. This provides a new framework for understanding how disturbances in membrane trafficking and lysosomal function are sensed and converted into disease-associated signalling. The importance of this mechanism is underscored by the discovery that mutations in Rab32, one of the recruiter Rabs, cause familial Parkinson’s disease and drive LRRK2 hyperactivation. Parkinson’s-associated LRRK2 mutations can also strengthen its interaction with recruiter Rabs, further promoting membrane recruitment and kinase activation. In addition, we have found that lysosomal damage and a Parkinson’s-associated mutation in the VPS35 retromer pathway recruit and activate LRRK2 at lysosomal membranes. This lecture will describe how human genetics, biochemistry, structural biology and cell biology are uncovering the mechanisms that recruit, activate and regulate LRRK2 during organelle stress. Understanding these pathways may reveal how endolysosomal dysfunction contributes to Parkinson’s and other neurodegenerative diseases, while opening new opportunities for biomarker development and therapeutic intervention.

Seminar room B1.16 
Meeting-ID: 665 7837 0338 Kenncode: 983709
Host: Thomas Jentsch