Inhibition of a key protein called dual leucine zipper kinase (DLK), a neuronal injury sensor, is protective in mice with amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease and shows potential for future therapeutic strategies, according to researchers.
The study, “Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease,” appeared in the journal Science Translational Medicine.
Despite recent advances in human genetics, the molecular pathways that lead to the degeneration of neurons in diseases such as ALS and Alzheimer’s remains poorly understood. But researchers believe that the mechanisms that neurons use to respond to chronic stress may be similar to those involved in neurodegenerative diseases, which may help understand the diseases and could in the development of new therapies.
Cumulative evidence has shown that DLK, which is predominant in neurons, is involved in diverse types of neuronal injury, and may be a key driver of neuronal degeneration. Absence of DLK protects against the degeneration of axons (long projections of neurons) and neuronal death.
DLK promotes either neuronal regeneration or death, depending on the cellular context. Therefore, targeting this protein may improve the outcome of neurodegenerative diseases.
The research was led by Joseph W. Lewcock, PhD, from the Department of Neuroscience at Genentech in South San Francisco, California. The study used molecular biology and imaging techniques to test whether deletion or inhibition of DLK may improve the neuronal stress response in models of ALS and Alzheimer’s.
Results revealed that mice and patients with ALS or Alzheimer’s had a cellular pathway (called the JNK pathway) activated, which was thought to be mediated by DLK. And indeed, when the team deleted the Dlk gene in mice, the activity of JNK was reduced.
Depleting the Dlk gene was shown to be neuroprotective in the transgenic superoxide dismutase 1 (SOD1)G93A mice, a model of ALS. Specifically, these mice showed protection against axon degeneration and neuronal death. Increased life span and motor strength were also found.
In addition, Dlk gene deletion showed protection against synaptic loss and cognitive decline in two mouse models of Alzheimer’s. The researchers also observed that Dlk deletion in adult mice improved learning, indicating protective effects even after JNK activation and accumulation of amyloid plaques, one of the hallmarks of Alzheimer’s.
The scientists further tested the injury-protective role of two synthetic inhibitors of DLK activity (GNE-8505 and GNE-3511). A single dose of GNE-8505 reduced JNK activation after optic nerve injury. The results also demonstrated that GNE-3511 administered three days after nerve injury served to weaken many of the alterations in gene expression.
In the SOD1G93A model of ALS, both inhibitors reduced activation of JNK, “even when disease-related JNK signaling had been present for weeks before drug treatment,” the researchers wrote. Notably, GNE-3511 delayed neuromuscular junction denervation (a sign of disease in this model) in mice aged between five and nine weeks.
This study shows “that pathological activation of DLK is a conserved mechanism that regulates neurodegeneration” in mice and human patients with ALS and Alzheimer’s.
“Given the consistent role for DLK/JNK signaling in multiple disease models driven by diverse mechanisms, DLK inhibitors hold broad therapeutic potential and may warrant advancement to clinical studies,” the researchers concluded.