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Structure of ALS molecule solved by MRC Laboratory of Molecular Biology, raising hopes of new treatments and diagnostic tools



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The structure of the molecule associated with ALS - the form of motor neurone disease that affected Professor Stephen Hawking - has been determined for the first time.

Led by scientists at the MRC Laboratory for Molecular Biology in Cambridge, the work is a vital step towards developing new therapies and diagnostic tests.

The cause of ALS - amyotrophic lateral sclerosis - is not clear, but a defining pathological hallmark of the disease is the abnormal clumping of a protein called TDP-43 in nerve cells.

The newly discovered structure of clumped TDP-43, from the brains of people with ALS. Picture: Benjamin Ryskeldi-Falcon/MRC Laboratory of Molecular Biology
The newly discovered structure of clumped TDP-43, from the brains of people with ALS. Picture: Benjamin Ryskeldi-Falcon/MRC Laboratory of Molecular Biology

ALS, the most common form of adult-onset motor neurone disease, leads to the deterioration of neurones that control voluntary muscle movements such as walking, talking, chewing and breathing.

TDP-43, which is found in healthy cells throughout our bodies, clumps together to form ‘aggregates’ in the brain in patients with ALS.

These clumps are also found in patients with frontotemporal dementia - the second most common form of early-onset dementia after Alzheimer’s disease - and are common in other neurodegenerative diseases, including Alzheimer's and Parkinson's.

While we have known this for some time, it has not been possible to translate this into potential therapies because the molecular structure of TDP-43 aggregates has not been known - until now.

Dr Benjamin Ryskeldi-Falcon, from the LMB, led the study, which used cryo-electron microscopy to determine the structure of TDP-43 (transactive response DNA-binding protein of 43kDa) aggregates extracted from the donated brains of two individuals who had ALS.

Dr Benjamin Ryskeldi-Falcon at the MRC Laboratory for Molecular Biology. Picture: MRC Laboratory of Molecular Biology
Dr Benjamin Ryskeldi-Falcon at the MRC Laboratory for Molecular Biology. Picture: MRC Laboratory of Molecular Biology

He said: “There are no diagnostics or therapeutics for ALS and other diseases associated with TDP-43 and the first step towards developing these is gaining a better understanding of TDP-43 itself.

“Now that we know what the structure of aggregated TDP-43 looks like and what makes it unique, we can use it to find better ways to diagnose the disease early.

“We’re excited to be able to use this blueprint in our lab to start identifying compounds that bind to unique sites on TDP-43, with the aim of identifying potential therapies for further study.

“I would especially like to thank the people with ALS, and their families, who donated their brains to research to help us gain a better understanding of this terrible disease.”

Benjamin and his group in the LMB’s Neurobiology Division worked with researchers at the Tokyo Metropolitan Institute of Medical Science and the Aichi Medical University in Japan on the study, which has been published in Nature.

Masato Hasegawa, from the Department of Brain and Neurosciences at Tokyo Metropolitan Institute of Medical Science, and Mari Yoshidaand, from the Institute for Medical Science of Aging at Aichi Medical University, provided Benjamin’s group with brain samples containing aggregated TDP-43 taken from the frontal and motor cortices of individuals with ALS and FTD.

The newly-discovered structure of clumped TDP-43, from the brains of people with ALS. Picture: Benjamin Ryskeldi-Falcon/MRC Laboratory of Molecular Biology
The newly-discovered structure of clumped TDP-43, from the brains of people with ALS. Picture: Benjamin Ryskeldi-Falcon/MRC Laboratory of Molecular Biology

Diana Arseni, a postdoc in Benjamin’s group, then carried out cryo-electron microscopy (cryo-EM) on the samples and, using helical reconstruction, exposed their structures up to resolutions of 2.6 angstrom (Å).

Analysis by Diana, Alexey Murzin and Benjamin revealed an amyloid-like helical filament structure comprised of stacked TDP-43 molecules.

They discovered that the structured filament core adopts a previously unseen double-spiral-shaped fold perpendicular to the helical axis.

While this structure of TDP-43 observed in the human brain samples was consistent in samples from different regions of the brains of both individuals, it was different from that seen in studies that attempted to recreate TDP-43 aggregates in a test tube.

They also found the filament core is formed by a region of TDP-43 with a low-complexity amino acid composition. This means the filaments’ surfaces are structurally and chemically different to those of other neurodegenerative disease-associated filaments formed by proteins such as tau and alpha-synuclein (α-synuclein).

Distinct molecules of currently unknown chemical identity were observed interacting with the surfaces of the filaments.

Dr Benjamin Ryskeldi-Falcon. Picture: Keith Heppell
Dr Benjamin Ryskeldi-Falcon. Picture: Keith Heppell

It had been thought that TDP-43 interacted like similar proteins associated with other neurodegenerative diseases such as Alzheimer’s, but the study suggests it is likely that the aggregation of TDP-43 results in different disease mechanisms.

These distinct structural features are thought to explain why current diagnostic tools, which rely on tracer compounds developed to bind to amyloid filaments, have proved poor at diagnosing ALS.

The research also suggests that since a single TDP-43 filament structure characterises both ALS and FTD, it could prove a viable new therapeutic target.

Dr Jo Latimer, head of neurosciences and mental health at the MRC, which funded the study, said: “These findings are an important and much needed contribution to our understanding of ALS and associated neurodegenerative diseases. Identifying the structure of a protein that is known to contribute to disease is the first step towards understanding its role in the development of disease.

“Currently, the cause of ALS is unclear but understanding the structure of TDP-43 will redefine how scientists think about disease progression and enable them to adopt entirely new approaches to developing therapies and diagnostics.”

The research was funded by the Medical Research Council and received support from Alzheimer's Research UK, the Japan Agency for Medical Research and Development and the Japan Science and Technology Agency.

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