Michel Goedert, a partner on the IMPRiND project, has recently published an article in Nature, describing the molecular structure of alpha-synuclein filaments in the brains of people with multiple system atrophy (MSA) or dementia with lewy bodies. IMPRiND, which stands for “Inhibiting Misfolded protein Propagation In Neurodegenerative Diseases”, is one of several projects in the IMI neurodegeneration portfolio aiming to decipher the molecular underpinnings of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. In particular, IMPRiND aims to map and target critical steps in the propagation of misfolded tau and α-synuclein proteins, considered the main culprits for neurodegeneration in Alzheimer’s and Parkinson’s disease, respectively.
The association between genetic alpha-synuclein mutations and inherited forms of Parkinson’s disease (PD) and dementia with lewy bodies (DLB) points to a causative role for alpha-synuclein in the development of these conditions. Previous studies have also identified damaging filaments of misfolded alpha-synuclein proteins inside the brain cells of people with PD and DLB. However, the molecular structures of these filaments have yet to be fully described.
To address this question, Michel Goedert and his team at the MRC Laboratory for Molecular Biology in Cambridge turned to Cryo-electron microscopy, a high-resolution technique that can reveal the 3D structure of proteins which measure less than a millionth of a centimetre in diameter. Using protein extracts from the brains of people with DLB or MSA (a condition with PD-like symptoms), they were able to show that alpha-synuclein filaments adopt distinct structural characteristics that vary between DLB and MSA. In addition, novel modifications to the alpha-synuclein filaments were identified, including the presence of non-protein molecules incorporated into the filaments.
These findings, which advance our understanding of how proteins are misfolded in synucleinopathies such as DLB and MSA, are an important step towards the development of PET tracers that could help diagnose these conditions, and the discovery of molecules which could prevent the formation of alpha-synuclein filaments during disease pathogenesis.
The paper can be accessed here: https://www.nature.com/articles/s41586-020-2317-6