Michel Goedert is a neuroscientist whose research studies the molecular mechanisms underlying human neurodegenerative diseases, such as Alzheimer's, Parkinson's, and related disorders. He is a Programme Leader at the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge, U.K., and an Emeritus Honorary Professor in the Department of Clinical Neurosciences at the University of Cambridge. His research established important roles for the proteins tau and alpha-synuclein in neurodegenerative diseases.

Early life and education Goedert was born in Luxembourg on May 22, 1954, where he was educated and lived until 1973. He then studied medicine at the University of Basel, receiving an MD degree in 1980. He subsequently moved to the University of Cambridge, where he obtained a PhD in 1984.

Career After completing his doctoral studies, Goedert joined the MRC Laboratory of Molecular Biology (LMB) in Cambridge as a postdoctoral scientist. He became a Programme Leader-track at the LMB in 1987 and Programme Leader in 1990. He subsequently joined the Laboratory's Neurobiology Division and served as its Head, jointly or alone, from 2003 to 2016. He was appointed an Honorary Professor at the University of Cambridge in 2014. Goedert has spent most of his research career at the MRC Laboratory of Molecular Biology, where he has led research into the molecular basis of neurodegenerative diseases. His work has combined molecular biology, biochemistry and structural biology to investigate the protein aggregates found in the brains of people with neurodegenerative disorders.

Research

Tau and Alzheimer's disease A major part of Goedert's research has concerned tau, a microtubule-associated protein found predominantly in neurons. Tau is involved in the organisation and stabilisation of microtubules, but abnormal forms of the protein can assemble into filamentous structures associated with neurodegeneration.

In 1986, Goedert began to collaborate with Claude Wischik, Tony Crowther, John Walker and Aaron Klug on determining the molecular nature of the paired helical filaments (PHFs) found in Alzheimer's disease. In 1988, they demonstrated that tau is a central component of these filaments. Goedert and colleagues subsequently characterised the molecular forms of tau that are being expressed in the human nervous system. They showed that the adult human brain contains six tau isoforms generated from a single gene through alternative messenger RNA splicing. These isoforms were found in the PHFs of Alzheimer's disease. This work helped establish tau pathology as a molecular feature shared by a number of neurodegenerative diseases. Tau-containing filamentous inclusions occur in Alzheimer's disease and in several other disorders collectively described as tauopathies, including progressive supranuclear palsy, corticobasal degeneration, Pick's disease and some forms of frontotemporal dementia.

Goedert also investigated the biochemical mechanisms underlying tau filament formation. His research examined the abnormal phosphorylation and assembly of tau and the effects of a number of molecules, including sulphated glycosaminoglycans, on tau aggregation.

MAPT mutations and inherited dementias In 1998, together with Maria Grazia Spillantini and Bernardino Ghetti, Goedert identified a mutation in MAPT, the gene encoding tau, in an inherited form of frontotemporal dementia with abundant filamentous tau inclusions. These findings provided genetic evidence that abnormalities in tau itself can cause neurodegeneration and dementia rather than merely occurring as a consequence of disease.

Subsequent work identified mutations and other genetic changes affecting MAPT and their relationships to different tauopathies. Goedert has also studied how altered tau isoform expression, abnormal phosphorylation and filament assembly contribute to neurodegenerative processes.

Prion-like spreading of assembled tau In 2009, together with Florence Clavaguera and Markus Tolnay, Goedert used transgenic mouse lines and intracerebral injection of tau filaments to demonstrate that assembled tau can seed aggregation in a given brain region, followed by the spreading of filamentous tau inclusions from the injection sites to anatomically connected brain regions. A few years later, they showed that the intracerebral injection of transgenic mice with brain homogenates from humans with Alzheimer's disease, tangle-only dementia, argyrophilic grain disease, progressive supranuclear palsy and corticobasal degeneration induces the formation of tau inclusions with the same light microscopic characteristics as in the human diseases.

Alpha-synuclein and Parkinson's disease Goedert's research also determined the molecular composition of the pathological inclusions associated with Parkinson's disease. In 1997, working with Maria Grazia Spillantini, Ross Jakes and other collaborators, he identified alpha-synuclein as the major component of Lewy bodies and Lewy neurites, the characteristic filamentous inclusions associated with Parkinson's disease and dementia with Lewy bodies. The discovery linked alpha-synuclein directly to the neuropathology of Parkinson's disease and established it as a central protein in a group of disorders now known as synucleinopathies. Goedert and colleagues subsequently identified multiple system atrophy as the third major synucleinopathy, extending the significance of alpha-synuclein pathology beyond Lewy body diseases. Research on alpha-synuclein has included its aggregation into amyloid filaments, the relationship between genetic alterations in SNCA, the gene encoding alpha-synuclein, and disease, as well as the structural properties of alpha-synuclein assemblies found in human brain tissues.

Structural biology and electron cryo-microscopy Since 2017, Goedert has been collaborating with Sjors Scheres of the LMB's Structural Studies Division. Their work uses electron cryo-microscopy (cryo-EM) to obtain the atomic structures of amyloid filaments extracted from human brains.

Their research showed that tau filaments associated with different neurodegenerative diseases can adopt distinct molecular structures. In 2021, they published a structure-based classification of tauopathies based on the conformations of pathological tau filaments.

In 2020, Goedert, Scheres and collaborators reported the atomic structures of alpha-synuclein filaments extracted from the brains of individuals with multiple system atrophy. Two years later, they determined the different structures of alpha-synuclein filaments extracted from human brains with Lewy pathology. This work provided structural information about disease-associated alpha-synuclein assemblies and contributed to the classification of synucleinopathies based on filament structures.

Goedert's group has also investigated amyloid-beta and TMEM106B filaments using cryo-EM. The research programme seeks to relate the structures of pathological protein assemblies to the different diseases in which they occur.

Mechanisms of tau filament formation More recent research has examined how tau molecules assemble into the filaments found in human neurodegenerative diseases. Goedert and collaborators have sought experimental systems capable of producing filaments that reproduce the structures observed in human brain tissue.

The LMB reports that their work has demonstrated that recombinant tau fragments can form filaments identical to PHFs isolated from Alzheimer's disease and other conditions. Similar work has been conducted with full-length tau carrying amino-acid substitutions designed to promote filament formation.

Disease classification Goedert's research has contributed to a molecular approach to classifying neurodegenerative diseases. Traditional classifications have often been based primarily on clinical symptoms and neuropathological features. Structural studies of tau and alpha-synuclein have provided additional criteria based on the conformations adopted by pathological protein filaments. The structure-based classification of tauopathies published by Goedert, Scheres and colleagues has demonstrated that different diseases are associated with characteristic tau filament folds. Their work has provided a framework for relating atomic structures of amyloid filaments to neuropathological and clinical disease categories. His research has similarly examined the structural diversity of alpha-synuclein filaments in Parkinson's disease and multiple system atrophy.

In recent work, Scheres, Goedert and colleagues report that the injection of tau filaments from the brains of individuals with Alzheimer's disease or corticobasal degeneration into the brains of wild-type mice results in the formation of cell type-specific tau inclusions characteristic of each disease and the formation of filaments of mouse tau with the same structures as those of the human seeds.

Beginnings In 2024, Michel Goedert published Beginnings: Looking back on twenty years in the Conseil de Gouvernance de l'Université du Luxembourg (Point Nemo Publishing), an illustrated semi-autobiographical account of the development of the University of Luxembourg and his involvement in its governance. Goedert served on the university's governing board from 2004 to 2023, and the book draws on his experience of the institution during its first two decades.

Personal life Goedert's partner is Professor Maria Grazia Spillantini, a neuroscientist, with whom he has a son, Thomas.

Awards and Honours

Metropolitan Life Foundation Award for Medical Research, 1996, shared with Yasuo Ihara, Virginia Lee, Brenda Milner and John Trojanowski Potamkin Prize for Pick's, Alzheimer's and Related Disorders, 1998, shared with Virginia Lee and John Trojanowski Member of the European Molecular Biology Organization, elected 1998 Fellow of the Royal Society, elected 2000 Prix Lions Luxembourg, 2002 Fellow of the Academy of Medical Sciences, elected 2006 European Grand Prix from the Fondation pour la Recherche sur Alzheimer, 2014 The Brain Prize, 2018, shared with Bart De Strooper, Christian Haass and John Hardy Royal Medal of the Royal Society, 2019 Rainwater Prize for Outstanding Innovation in Neurodegenerative Research, 2020 Piepenbrock-DZNE Prize, 2021 Annemarie Opprecht Foundation Parkinson Award, 2023, shared with Sjors Scheres Karl Golser Foundation Award, 2024 Honorary Member, Institut Grand-Ducal, Section des Sciences, Luxembourg, 2025 Helis Foundation Award for Parkinson's Disease and Neurodegenerative Research, 2026

References

External links Dr Michel Goedert

http://www.prion2014.org/images/bio_Goedert.pdf