3D structures of tau and alpha-synuclein proteins vary by brain disease, several studies show

Thanks to family members who donated brain tissues from their deceased loved ones, a team of scientists from the United Kingdom, Japan, and the United States compared the 3D structures of protein filaments extracted from several types of degenerative brain disease. These research projects revealed that each brain disease is associated with a unique 3D filament structure of tau or alpha-synuclein protein. The discovery of disease-specific filament structures could be translated into better detection and treatment methods.

The research team used cryogenic electron microscopy, which enables the discovery of 3D structures of proteins and other molecules. Subtle differences in the building blocks of a protein such as tau or alpha-synuclein can cause the structure to bend, fold, or twist in a new way. Previous research by the team, reported in Nature and Acta Neuropathologica, revealed the 3D structures of tau filaments from people with Alzheimer’s disease and Pick’s disease, a form of frontotemporal degeneration. The studies demonstrated that the 3D structures vary by disease. The more recent studies, which were reported in three Nature articles, extended this work by determining 3D structures for protein filaments from other brain diseases.

After conducting studies of Alzheimer’s disease and Pick’s disease, the team determined 3D structures of tau filaments from the brains of three individuals affected by chronic traumatic encephalopathy (CTE), which is a condition associated with repeated head injuries from boxing, football, or other activities. The tau filament structures were the same among people with CTE. But the tau filament structure from CTE was different from tau filaments from Alzheimer’s disease and Pick’s disease.

For the next study, the researchers extracted tau filaments from three individuals who had a brain disease called corticobasal degeneration (CBD). They reported that tau structures were identical among people with CBD but different from tau structures from people with Alzheimer’s disease, Pick’s disease, and CTE.

Just as the presence of abnormal tau protein filaments are associated with certain brain diseases, the presence of filaments of alpha-synuclein protein are associated with Parkinson’s disease, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). For the most recent study, filaments of alpha-synuclein were extracted from the brains of three people who had DLB and five people who had MSA. Just as the research team had observed among tau filament structures, the researchers showed that the structures of alpha-synuclein filaments from the brains of people who had MSA differed from those who had DLB.

By better understanding what causes the differences between protein filaments associated with brain diseases, new ways of diagnosing and treating these diseases may be developed. For example, knowing the unique structure of tau and alpha-synuclein can aid the development of tests for early diagnosis and differentiation from similar brain diseases. Similarly, understanding how the toxic filament bends and twists can aid researchers in exploring the role that a specific structure plays in disease development. Solving that mystery could help researchers design a treatment that prevents the formation of toxic forms of tau and alpha-synuclein proteins.

The six research studies were funded in part by NIA. Coauthors Drs. Bernadino Ghetti and Kathy L. Newell, who are in the Dementia Laboratory of the Department of Pathology and Laboratory Medicine at Indiana University, analyzed the brain tissue samples from people with Alzheimer’s disease, Pick’s disease, and CTE, as well as some of the samples from people with CBD. The laboratory is supported in part by NIA grants, including grant P30AG010133 for the Indiana Alzheimer Disease Center and U01NS110437.

These activities relate to the following NIA AD+ADRD Research Implementation Milestones:

• 2.H. “Continue to support cross-disciplinary research to discover and understand disease mechanisms that are common between AD and other neurodegenerative disorders including rare disorders and leverage these for therapy development.”
• 2.N. “Clarify unique and converging cellular mechanisms related to tau pathogenesis, C9orf72 hexanucleotide repeat expansions, GRN mutations, and other targets and pathways contributing to FTD neurodegeneration.”

References: Fitzpatrick A, et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature. 2017;13;547(7662):185-190.

Falcon B, et al. Structures of filaments from Pick's disease reveal a novel tau protein fold. Nature. 2018;561(7721):137-140. doi: 10.1038/s41586-018-0454-y.

Falcon B, et al. Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold. Acta Neuropathologica. 2018;136(5):699-708. doi: 10.1007/s00401-018-1914-z.

Falcon B, et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature. 2019;568(7752):420-423. doi: 10.1038/s41586-019-1026-5.

Zhang W, et al. Novel tau filament fold in corticobasal degeneration. Nature. 2020;580(7802):283-287. doi: 10.1038/s41586-020-2043-0.

Schweighauser M, et al. Structures of α-synuclein filaments from multiple system atrophy. Nature. 2020. ePub May 27. doi: 10.1038/s41586-020-2317-6.