Scientists have discovered for the first time the structure of the molecule associated with amyotrophic lateral sclerosis (ALS) and numerous other neurodegenerative illnesses. This discovery, according to the researchers at the Medical Research Council (MRC) Laboratory for Molecular Biology in Cambridge, UK, could allow for the focused development of new medical interventions and diagnostic tests.
ALS is the most prevalent type of adult-onset motor neuron disease, and it is marked by the loss of neurons that govern voluntary muscular movements including walking, talking, chewing, and breathing.
There is no cure for ALS, and there is no effective treatment that can slow or stop the illness from progressing. While the cause of ALS is unknown, the aberrant clumping of a protein called TDP-43 in nerve cells is the disease’s distinguishing pathological signature.
TDP-43 aggregates are also found in other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s, and are a characteristic of frontotemporal dementia (the second most common form of early-onset dementia after Alzheimer’s disease).
TDP-43 is abundant in healthy cells throughout our bodies, but it clumps together in the brains of patients with certain disorders, forming ‘aggregates.’
Although scientists have known about this for some time, the ability to turn this knowledge into treatments has been limited because the chemical structure of TDP-43 aggregates has remained unclear until recently.
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.
Dr. Benjamin Ryskeldi-Falcon
Now, scientists from the MRC Laboratory for Molecular Biology have used cryo-electron microscopy to determine the first molecular structure of TDP-43 aggregates extracted from the donated brains of two people with ALS, in collaboration with researchers from the Tokyo Metropolitan Institute of Medical Science and Aichi Medical University in Japan.
The study, which was funded by the Medical Research Council and published in Nature, uncovered previously unknown structural elements such a filamentous double-spiral-shaped fold.
TDP-43 structure was constant in samples from different parts of both individuals’ brains in this investigation, but it differed from that seen in prior studies that attempted to reproduce TDP-43 aggregates in a test tube.
TDP-43 was previously assumed to interact in the same way as homologous proteins linked to other neurodegenerative disorders including Alzheimer’s. TDP-43 aggregation, on the other hand, appears to result in a variety of disease mechanisms, according to this study.
TDP-43 in the brain is anticipated to interact differently with diagnostic instruments and medications because to its particular structural properties. These discrepancies, according to the researchers, may explain why current diagnostic chemicals based on comparable proteins linked to other neurodegenerative illnesses are ineffective in identifying ALS.
The findings open up new avenues for the development of therapeutics based on chemicals that target structural characteristics of TDP-43, particularly those that cause aggregation.
Dr. Benjamin Ryskeldi-Falcon, from the MRC Laboratory for Molecular Biology, who led the study, 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.”
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 study was supported by Alzheimer’s Research UK, the Japan Agency for Medical Research and Development, and the Japan Science and Technology Agency, as well as the Medical Research Council.
