Blocking MAP4Ks proteins extends survival in ALS mouse model
Researchers believe it can be tweaked to better reach brain, boost efficacy
A new compound that significantly extended survival in a mouse model of amyotrophic lateral sclerosis (ALS) by blocking the activity of a group of proteins called MAP4Ks has been identified by researchers.
The molecule was associated with modest benefits, but researchers believe it can be tweaked to improve its ability to reach the brain and boost its effectiveness, potentially acting as a future treatment candidate for ALS.
“This study will significantly advance the ALS field by providing a leading compound and a signaling pathway for future investigations,” Chun-Li Zhang, PhD, co-author of the study at the University of Texas Southwestern Medical Center, Dallas, said in a university press release. The study, “Screens in aging-relevant human ALS-motor neurons identify MAP4Ks as therapeutic targets for the disease,” was published in Cell Death and Disease.
ALS is marked by the progressive death and dysfunction of motor neurons, the nerve cells that control voluntary movements. Finding ways to keep motor neurons healthy is a major priority for ALS research.
Because motor neurons can’t be collected directly from patients for study, scientists commonly rely on indirect cell models. One of the most common models involves using motor neurons derived from induced pluripotent stem cells (iPSCs). This involves taking skin or cells from a patient, reverse engineering them into stem cells and growing them into motor neurons.
One drawback of this method is that in the stem cell step, iPSC-derived motor neurons lose cellular markers of age. Given that ALS usually affects people in middle to late adulthood, this means iPSC-derived motor neurons won’t have the age-related markers seen in patients’ motor neurons that could be promising targets for new therapeutics.
A research team led by scientists at UT Southwestern previously developed a method whereby skin cells can be directly engineered to grow into motor neurons, an approach that provides a motor neuron cell model that maintains its age-related markers. They previously showed this approach could aid in making motor neurons out of skin cells from people with ALS. As would be expected, neurons derived from ALS patients had disease features and were less functional than those from healthy people.
Treating motor neurons with Hit3
Here, they used the new cell model to screen a library of roughly 2,000 medications and other biologically active compounds to look for substances that could improve the health of ALS motor neurons.
The screen and subsequent follow-up tests identified a compound dubbed Hit3. ALS motor neurons treated with Hit3 more closely resembled normal motor neurons and were better able to form healthy connections with muscle cells.
“Hit3 could remarkably rescue both the morphological and functional deficits of ALS-hiMNs [motor neurons derived from people with ALS],” wrote the researchers, who determined in further experiments that Hit3 exerts its protective effects in ALS motor neurons by blocking the activity of a group of proteins called MAP4Ks, short for mitogen-activated protein kinase kinase kinase kinases.
Blocking MAP4K activity sets off a chain of molecular events that appears to promote nerve health and function. These effects were seen both in cells from people with ALS and from healthy people.
The researchers next tested the effect of blocking MAP4Ks in a mouse model of ALS caused by a mutation in SOD1, a genetic form of the disease that’s typically more aggressive. For these experiments, they used a MAP4K inhibitor (MAP4Ki) called PF6260933, which was chosen instead of Hit3 because it could reach higher concentrations in the blood and nervous systems in mice.
The treatment significantly extended their lifespan. The median survival was 139 days with MAP4Ki compared with 129 days in mice given an inactive vehicle. Treated mice also had less motor neuron damage.
Although MAP4Ki itself isn’t well suited for people — it degrades quickly and isn’t able to cross into the brain to target nerve cells — the results support the idea that blocking MAP4K activity may be therapeutically beneficial in ALS.
“Even though MAP4Ki extended survival by just a short time, our results suggest treatments that block the MAP4K pathway could one day be useful therapeutically,” Zhang said.
More research “to develop more potent blood-brain barrier-penetrating MAP4K inhibitors for ALS and other neurodegenerative diseases” is needed, the researchers said.
About the Author
