Suppressing an enzyme known as MAP4K4 extended the survival of motor neurons collected from mice and patients with amyotrophic lateral sclerosis (ALS), and decreased the accumulation of toxic proteins associated with the disease, a study reports.
These findings from the study, titled “MAP4K4 Activation Mediates Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis,” indicate that MAP4K4 could be a potential target for the treatment of ALS. It was published in the journal Cell Reports.
Inhibition of MAP4K4 has been associated with extended survival of human motor neurons, the specialized cells that are progressively lost in ALS. Although both the molecular pathway involving this enzyme and its role in insulin resistance, innate immune response, and sensory neuron survival have been described, data is scarce on the effects of MAP4K4 on motor neurons.
To address this lack of information, a research team from Harvard University conducted a variety of cell cultures, genetic manipulation, and imaging experiments focusing on the role of MAP4K4 in motor neuron survival. Besides spinal motor neurons and embryonic stem cells from mice, the investigators also used induced pluripotent stem cells, which are reverted to an embryonic-like state able to grow into all cell types, collected from ALS patients.
Results revealed that MAP4K4 signaling is activated in both healthy controls and ALS motor neurons from mice. MAP4K4 activation preceded the lower survival of ALS neurons compared with the controls.
The scientists then found that reducing the levels of MAP4K4 with RNA molecules called small interfering RNAs (siRNAs) increased survival of both control and ALS mouse motor neurons in a dose-dependent manner. A similar benefit was observed in stem cell-derived human motor neurons, especially in those carrying the SOD1L144F mutation, which was previously reported in ALS patients.
Findings also revealed that MAP4K4 induced apoptosis — meaning “programmed” cell death, as opposed to death caused by injury — of motor neurons via activation of JNK3 (mainly found in the central nervous system and proposed as a therapeutic target in Alzheimer’s and Parkinson’s) and c-Jun.
Inhibition of MAP4K4 also prevented the degeneration of neurites — projections from the cell body, whose degeneration is an early symptom of neuronal disorders — and lessened the accumulation of mutant SOD1 protein, which underlies approximately 20% of familial ALS cases.
Levels of ubiquitin — a marker for protein degradation — were also lowered in patient-derived motor neurons. These effects were associated with activation of autophagy, a cellular process to remove aggregated and toxic proteins.
Subsequent experiments revealed that a selective inhibitor of MAP4K4 prolonged human and mouse motor neuron survival under different stress conditions, particularly in ALS motor neurons. Similar benefits were found in motor neurons collected from mice’s spinal cords, showing a more pronounced effect in cells carrying the SOD1G93A mutation.
“These data cumulatively reinforce the idea that MAP4K4 can be a druggable target for ALS and provide a strong rationale for testing whether MAP4K4i is protective in vivo as well,” the scientists wrote. “MAP4K4 can potentially be broadly therapeutic for a variety of other [motor neuron] and neurodegenerative disorders.”