Results from scientific research looking into STMN2 – a potential novel biomarker and drug target for amyotrophic lateral sclerosis
Summary by Anushka Bhargava, PhD student, the University of Sheffield
ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. DOI: 10.1038/s41593-018-0300-4
11 January 2019
Amyotrophic Lateral Sclerosis (ALS), more commonly known in the UK as motor neurone disease, is a rare and progressive brain disorder in which neurons responsible for controlling voluntary muscle movement (motor neurons) progressively deteriorate. Loss of affected neurons leads to muscle wasting, paralysis, and eventual death due to failure to breathe. Most patients are unable to survive past five years following a long diagnostic journey. Due to the complexity of the disease mechanism, the progression of the disease is highly variable, proceeding in affected individuals with different aggressiveness and velocity. There is no known cure for ALS and a robust diagnostic test for ALS is essential. For this, scientists are constantly in search of reliable biological markers of the disease.
The exact cause of the disease is yet to be determined, however, several studies and research over the years have indicated that patients almost universally display abnormal mislocalization of a protein called TAR DNA-binding protein 43 (TDP-43). As the name suggests, this protein binds to deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) which are the molecules vital for protein production. DNA is a double-stranded helix that contains the genetic code for a cell’s activities, whereas RNA converts that code into proteins to carry out cellular functions. It is noteworthy that DNA also codes for RNA.
A cell contains a central compartment where the DNA is stored called the nucleus and outside, the nucleus is surrounded by a thick solution that fills up the cell called the cytoplasm. TDP-43 should originally reside in the nucleus of neurons but instead, in disease, this is flushed out into the cytoplasm where it builds up into aggregates. Since these aggregates are found in ALS patients, they have been a well-known hallmark of the disease. Mutations, or changes, in the TDP-43 gene, cause familial ALS, a type of ALS which can be passed on through generations. Researchers have proposed that mutations in this gene alter the processing of RNA in the cell, which is proposed to be a disease mechanism. However, the RNAs in motor neurons that are modulated by TDP-43 and their consequent impact on disease are yet to be determined.
What did the authors do and how did they do it?
The researchers involved in the paper identified all the possible types of RNA molecules that undergo changes in their levels in human neurons due to sensitivity to TDP-43 depletion. This was done in the context of human neurons where human stem cells were used and grown into motor neurons. This is significant as previously this has only been attempted in cells obtained from mice or cancer cells lines.
The researchers identified 885 RNA molecules that were affected by TDP43 and of them, they selected a few to look further into. They selected RNA molecules specifically produced in neurons, those that were associated previously with neurodevelopment/neurological disorders and those with large changes in levels.
What are the results?
It was reported that the production of the protein from the Stathmin2 (STMN2) gene was affected due to TDP43 depletion, in the human stem cell model. It was shown that when there was a decrease in TDP43 levels, there was a significant decrease in the abundance of STMN2. This indicated a direct specific relationship between TDP43 and STMN2. This finding was further validated postmortem patient spinal cord tissue. This highlights how well the human stem cell model predicted what happens in ALS patients.
The STMN2 gene is a critical gene that codes for a protein that is important for neurite outgrowth and repair. Neurite outgrowth is a process where developing neurons produce new projections as they grow. STMN2 levels changed consistently with the manipulation of TDP-43, where reduced TDP-43 function caused functional STMN2 loss. It was observed that without TDP-43, the instructions for making the functional STM2 protein were jumbled and turned into nonsense and therefore produced a non-functional STMN2 protein. This in turn meant that STMN2 could no longer assist in the vital processes for repairing and growing motor neuron projections.
With the perspective that STMN2’s non-functional protein caused by TDP43 depletion may play a role in motor neuron damage, the researchers went on to test if whether fixing STMN2 could rescue this. Notably, it was found that correcting the jumbled instructions of STMN2 rescued neurite outgrowth and regeneration of projections that was otherwise affected by TDP-43 depletion. With this data, they propose that restoring functional STMN2 may be a potential therapeutic strategy for ALS. Moreover, the study also points towards a potential new biological marker and drug target for ALS.
Why is the study important? What do the finding mean going forward for people with the disease?
This study holds great importance in the field of human disease models as wells as ALS. Firstly, the research highlights the significance of using human stem cell models for ALS. Findings in mice are rarely applicable in humans and therefore findings in this paper would have been missed if a mouse model of ALS was used. The stem cell model used in the study successfully encompassed the relationship between TDP-43 and STMN2. This shows how relevant the stem cell models can be and their value in therapeutic strategy discovery. Secondly, the direct relationship between TDP-43 and STMN2 hints towards a possible pathway of TDP-43 mutation that might lead to motor neuron loss in ALS. It aids in explaining a possible disease mechanism for ALS. Lastly, STMN2 appears to be a promising therapeutic target for ALS patients. The series of experiments in the paper point out that repairing STMN2 in patients can potentially slow or stop the loss of motor neurons. The research suggests a clear approach for developing a potential therapy for ALS. Furthermore, STMN2 could be the first biological marker for most patients with ALS. This means that checking for a decrease in abundance of STMN2, loss of functional STMN2 protein, or looking for the jumbled protein-making instructions for STMN2 could be used as a diagnostic tool for ALS.
This study can be found at www.nature.com/articles/s41593-018-0300-4