A specific mutation to the microtubule affinity regulating kinase 4 (MARK4) enzyme could change the properties of the protein tau present in the human brain cells leading to Alzheimer’s disease, find the researchers from Tokyo Metropolitan University, Japan.
Alzheimer’s is said to be caused by the build-up of tangled clumps of the tau protein within the brain cells. These sticky aggregates cause neurons to die, leading to impairment in memory and motor functions.
Tau is a protein that helps stabilize the internal cytoskeleton of nerve cells in the brain. MARK4 is a novel microtubule-associated proteins/microtubule affinity-regulating kinase that binds to the cellular microtubule network and to centrosomes.
MARK4 expression is found to be elevated in the brains of AD patients, and its activity colocalizes with early pathological changes. In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser262 and Ser356 play critical roles in tau accumulation and toxicity. MARK4 was found to phosphorylate tau at those sites, and a double de novo mutation in the linker region of MARK4, ΔG316E317D, was found to be associated with an elevated risk of AD.
A team led by Associate Professor Kanae Ando of Tokyo Metropolitan University compared the effects of MARK4 carrying the ΔG316, E317D mutation (MARK4ΔG316E317D) on tau accumulation. The study showed that in transgenic drosophila that the mutant version of MARK4 (MARK4ΔG316E317D) the total tau levels and tau-induced neurodegeneration was enhanced. The co-expression of the mutated form with the human MARK4 enzyme ( MARK4wt) further increased the accumulation and toxicity of tau.
The modified tau had an excess of certain chemical groups that caused it to misfold, they found that it aggregated much more easily and were no longer soluble in detergents. This made it easier for tau to form the tangled clumps that cause neurons to degenerate.
The findings may lead to new treatments and preventative measures for an even wider variety of neurodegenerative conditions.