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My Name’5 Doddie Foundation invests in pilot study investigating the potential link between heavy chain neurofilament and TDP-43 pathology

02 October 2023

The Foundation is investing up to £50,000 in a new pilot study led by Professors Andrea Malaspina and Giampietro Schiavo, University College London. With their co-investigator, Dr Ian Pike of Proteome Sciences, they will investigate whether the expression of a protein called heavy chain neurofilament (NfH) is implicated in TDP-43 protein disorder, a pathological hallmark in MND. 

Neurofilaments and TDP-43

Key components of motor neurons are proteins called neurofilaments. Specifically, they are found in the axon, the long structure that transmits information away from the cell body and towards other motor neurons. Neurofilaments, comprising three chains - light (NfL), medium (NfM) and heavy (NfH) - give stability to the axon and aid in the transport of multiple factors from the cell body to the nerve ending. A fine balance of the level of NfL, NfM and NfH is important to maintain axonal function, and this balance is believed to be disrupted in motor neurons of people living with MND.

Recent evidence suggests a direct link between changes in neurofilaments and a protein called TDP-43. This protein is usually found in the nucleus of healthy motor neurons, where it plays a role in regulating new proteins made by the cell. In MND, TDP-43 is often mis-localised outside of the nucleus, where it forms toxic clumps. It has been suggested that TDP-43 dysregulation may be facilitated by changes in NfH expression in the motor neurons and that an excess of NfH is present in cells with TDP-43 pathology.

This project will investigate whether modification of NfH expression in motor neurons reduces TDP-43 pathology, thus exploring the possibility of a link between NfH expression and the dysregulation of TDP-43.

Induced pluripotent stem cells

In this project, Professor Malaspina will use a powerful research tool called induced pluripotent stem cells (iPSCs). These are cells that have been taken from human tissue (usually skin) and re-programmed in the lab into a specific cell of interest (in this case, motor neurons). First, well-established methods will be used to turn skin cells from people living with MND, into pluripotent stem cells, which are embryonic-like cells capable of developing into several different cell types. Specific growth factors will then be applied to turn the pluripotent stem cells into motor neurons.

iPSCs derived from people living with genetic MND, carry the same genetic alterations that lead to the development of MND. They display many of the characteristics of diseased motor neurons in the human body, making them an excellent research tool. This project will use iPSCs with a specific mutation in TDP-43, which causes TDP-43 protein dysregulation.

Potential impact

A greater understanding of the effects that the modulation of NfH expression in motor neurons entails and its potential link with TDP-43 regulation could open new therapeutic avenues. If the research finds that lowering NfH levels in motor neurons reduces TDP-43 pathology, new treatments to reduce the levels of NfH in motor neurons could be explored. Over 90% of people living with MND show features of TDP-43 pathology, so unraveling this link could be beneficial to the treatment pipeline for most people living with the disease.

What’s more, if a specific expression pattern of NfH is found in the motor neurons of people living with MND, this observation could lead to the use of NfH as a biomarker to stratify people with ALS based on disease progression, or to monitor the effectiveness of novel treatments.

Professor Malaspina said “In my view, one of the most rewarding lines of research in ALS is the identification of molecules that could be targeted by novel therapeutics and at the same time, used for diagnosis and monitoring of the disease process. In this project, we will focus on a neurofilament protein that may undermine the resilience of the motor cells to withstand pathological changes associated with ALS and represent a good biomarker of the same pathological process.”

We would like to thank all our supporters who make it possible for us to support work like Professor Malaspina’s. Donate to the Foundation here to allow us to continue supporting vital research into a cure for MND.


My Name’5 Doddie Foundation invests in pilot study investigating the potential link between heavy chain neurofilament and TDP-43 pathology
My Name’5 Doddie Foundation invests in pilot study investigating the potential link between heavy chain neurofilament and TDP-43 pathology

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