Sofia Lövestam, postdoctoral researcher at the LMB, has been announced as one of the 2024 winners of the Harold M. Weintraub Graduate Student Award in recognition of her Ph.D. work investigating the protein structures behind neurodegenerative diseases. The award is given by the Fred Hutchinson Cancer Center based in Seattle, USA and seeks to recognise “outstanding achievement during graduate studies in the biological sciences.”
The award’s namesake, Harold (Hal) M. Weintraub made significant contributions to the understanding of how gene expression leads to cell differentiation; work which helped found the modern field of epigenetics. Hal himself was an LMB alumnus, having arrived in the LMB’s Cell Biology Division as a Scientific Visitor in the early 1970s. Hal left the LMB for Princeton University before joining the Basic Sciences Division at Fred Hutch in 1978. He remained a member of this Division until his death in 1995 at the age of 49.
Sofia joined the LMB as a Ph.D. student in 2019, working with Sjors Scheres’ group in the Structural Studies Division and Michel Goedert’s group in the Neurobiology Division. The groups’ collaborative studies have determined the structures of several amyloids from filamentous protein aggregates, the accumulation of which characterise different neurodegenerative diseases. Historically, this research has relied on studying amyloid filaments from post-mortem brains, which presents its own limitations. To tackle this, Sofia’s Ph.D. focused on developing in vitro amyloid assembly reactions to replicate the same structures observed in diseases brains.
It had previously been assumed that progressive accumulation of amyloids occurred through prion-like spreading, whereby existing filaments provide seeds that template the growth of further filaments. However, when Sofia first mapped the structures of the in vitro seeded assembly of recombination alpha-synuclein filaments with seeds from brains with Multiple System Atrophy (MSA), she surprisingly found they yielded new structures. Her paper detailing this discovery was recognised with the 2022 FEBS Open Bio Article Prize.
Sofia then shifted focus to tau filaments, setting out to use spontaneous in vitro assembly of recombinant tau to make the same structures as those observed in brains afflicted with different tauopathies. This required exploration of a large number of methods and conditions to make tau filaments, and a huge amount of time analysing them using electron cryo-microscopy (cryo-EM). She successfully identified truncated tau constructs and in vitro assembly conditions which created identical tau filaments to those found in Alzheimer’s Disease (AD) and Chronic Traumatic Encephalopathy (CTE). This accomplishment has vast potential to expand access to several researchers looking to study these diseases. To this end, Sofia has shipped her tau constructs to laboratories all over the world, and has provided guidance to help several research groups replicate her results.
Building on these results, Sofia next turned her attention to analyse the molecular mechanisms of amyloid formation in AD and CTE in a time-dependent manner. Contrary to prevailing opinion, she found that tau assembles through many intermediate structures. She also discovered a shared First Intermediate Amyloid (FIA) present in the pathway towards AD and CTE filaments. Her study provides the first tangible structural characterisation of intermediates of amyloid filament formation, and has revealed a complexity to this process that had not been previously predicted.
Throughout her Ph.D., Sofia used cryo-EM to solve over 300 structures of amyloid filaments. She has expanded understanding of the molecular mechanisms which drive amyloid formation, and has discovered several new avenues of research for the field. Ultimately, this could prove crucial in the design of new drugs to target different neurodegenerative diseases. Her work has previously been recognised with the 2022 Perutz Student Prize.
Further references
Harold M. Weintraub Graduate Student Award 2024
Sjors’ group page
Michel’s group page