MRC LMB in Cambridge solves neurodegeneration debate with amyloid finding

New research from Benjamin Ryskeldi-Falcon’s group in the Neurobiology Division at the MRC Laboratory of Molecular Biology in Cambridge has resolved a longstanding debate in the study of neurodegeneration.

They found that distinct filament folds of TAR DNA-binding protein 43 (TDP-43) characterise different neurodegenerative conditions.

It was not known if TDP-43 formed amyloid filaments in diseases beyond amyotrophic lateral sclerosis (ALS). The abnormal assembly of the protein is believed to be responsible for almost all cases of ALS and around half of cases of frontotemporal dementia (FTD).

At least four types of frontotemporal degeneration with TDP-43 pathology (FTLD-TDP) are known to be defined by distinct brain distributions of the assembled protein, and they lead to differing clinical presentations of FTD.

Lead author Diana Arseni, a postdoc in Benjamin’s group, used electron cryo-microscopy (cryo-EM) to determine the structures of assembled TDP-43 from the brains of individuals with type A FTLD-TDP, the most common variation.

The LMB said: “The cryo-EM analysis also demonstrated the existence of structural variation within individual TDP-43 filaments.

“This shows that amyloid filaments do not always adopt uniform repetitive structures, which has implications for the development of diagnostic and therapeutic tools that target these filaments.

“Currently, there are no effective disease-modifying therapies for ALS or FTD, and no way to diagnose these diseases early enough to allow for impactful therapeutic intervention.

“This research will guide studies into the molecular mechanisms of TDP-43 assembly, as well as the development of tools that target distinct TDP-43 filament folds for early diagnosis and, possibly, treatment of ALS and FTD.”

They also identified two new post-translational modifications of TDP-43.