Loss of STMN2 Protein Contributes to ALS Progression, Study Finds
TDP-43 protein abnormalities characteristic of most amyotrophic lateral sclerosis (ALS) cases contribute to the loss of motor neurons mostly by limiting the function of a protein called stathmin-2 (STMN2), a study reported.
Results indicate that boosting STMN2 levels may be a useful approach in treating ALS, according to its researchers.
“The demonstration that STMN2 is a functionally relevant target is an important step forward for the development of rational treatments for this devastating disease,” the team wrote.
Of note, an experimental therapy called QRL-201 that aims to raise STMN2 production is expected to enter clinical trials this year. The company developing that therapy, QurAlis, was not involved in the work reported here.
The study, “Loss of Stathmin-2, a hallmark of TDP-43-associated ALS, causes motor neuropathy,” was published in Cell Reports.
ALS is characterized by the dysfunction and death of motor neurons, the nerve cells that control movement. One of the molecular features found in nearly all ALS patients is abnormal clumps of the TDP-43 protein in nerve cells, which are believed to contribute to disease progression.
STMN2 essential for nerve cell growth, repair
TDP-43 normally helps to regulate RNA splicing, basically controlling which parts of certain genes are “read” to create proteins. Prior research has suggested that, in ALS cells with TDP-43 abnormalities, these changes lead to reduced production of STMN2, a protein essential for neuronal growth and repair.
Scientists conducted a series of experiments to test whether lower STMN2 levels as a consequence of TDP-43 dysfunction might contribute to ALS progression. The team included several employees of Disarm Therapeutics, a company now owned by Eli Lilly.
In initial cell experiments, the researchers showed that reduced STMN2 levels cause abnormalities in the growth of axons — the long, wire-like structures that nerve cells use to connect with each other and the rest of the body.
Using genetic engineering, the scientists created STMN2 “knockout” mice unable to make this protein in any of their cells. They also created mice where the knockout was restricted to motor neurons, with all other cell types retaining the ability to make STMN2.
Higher death rates were evident in the knockout mice in the first weeks following birth compared with their healthy counterparts, but those that survived to adulthood “seem to be healthy with grossly normal behavior,” the researchers reported. Motor function assessments, however, revealed that the mice’s grip strength and ability to sense touch were “profoundly impaired.”
Analyses of the mice’s nerves showed no alterations in the number of axons or any apparent differences in axonal health in the knockout mice. However, the researchers found notable differences in the mice’s neuromuscular junctions (NMJs), the site where the end of an axon comes into contact with a muscle cell.
Pattern of motor problems mirrors ALS progression
Normally, the NMJ is a highly organized structure where the nerve cell can secrete signaling molecules that are detected by receptor proteins on the muscle cell, thereby controlling muscle contractions. But in the knockout mice, the NMJ “is severely disorganized,” the researchers wrote.
In fact, it was so disorganized that the researchers had trouble telling which nerves were signaling to which muscle cells in knockout mice, whereas these connections are typically very clear in healthy mice.
According to the scientists, this probably reflects degeneration in the furthermost part of the nerve that makes contact with the NMJ, referred to as presynaptic degeneration. NMJs further from the center of the body (e.g., in the hind feet) were more severely affected, which is also generally the pattern of motor dysfunction seen in people with ALS.
Notably, motor function and NMJ defects seen in mice lacking STMN2 only in their motor neurons were generally similar to those seen in mice lacking the protein in all their cells. This suggests that the effect of the protein on motor neurons is cell-autonomous, meaning the cell is dependent on its own supply of the protein.
“These data do not exclude the potential involvement of other cell types, but, importantly, they demonstrate that there is a cell-autonomous requirement for STMN2 in [motor neurons] and that the loss of STMN2 in [motor neurons] is sufficient to cause a distal motor neuropathy,” the scientists wrote.
Researchers next engineered mice that would produce the STMN2 protein but at lower levels than normal, akin to what is seen in people with ALS. These mice had normal motor function and NMJ function as young adults, but gradually developed motor weakness and showed signs of presynaptic degeneration at NMJs as they aged.
“These data strongly support the hypothesis that a decrease in STMN2 protein levels contributes to ALS pathology [disease development] and suggests that the restoration of normal STMN2 protein levels in patients with ALS with TDP-43 pathology could promote [NMJ] maintenance and motor function,” the scientists concluded.
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