Alex Dean

New target for Alzheimer’s disease-MSUT2

Blog Post created by Alex Dean on Feb 28, 2020

After A string of disappointing clinical trials targeting the amyloid β-protein(Aβ), researchers in the field of Alzheimer’s disease (AD) are paying more attention to the tau protein, another culprit in the disease. Like Aβ, Tau protein accumulates in the brains of AD patients and damages brain cells. The correlation between the protein and AD originated from a discovery more than 100 years ago: research revealed that Tau protein is the main component of neuron fiber tangles characteristic of AD pathology. Although the industry has generally believed that Tau aggregation is only the result of the development of AD disease, some new developments have slowly confirmed that tau aggregation may be a causative factor for AD.

In a new study, researchers from the University of Washington school of medicine and the veteran’s affairs Puget sound health system, among others, found promise in targeting abnormal tau proteins by suppressing a gene called mammalian suppressor of tauopathy 2(MSUT2). They concluded that as long as an RNA-binding protein called PABPN1 (PolyA Binding Protein Nuclear 1) is not depleted, inhibiting MSUT2 may protect people from Alzheimer’s disease. MSUT2 and PABPNI usually work closely together to regulate the biological properties of tau in the brain. Related research results were recently published in the journal Science Translational Medicine, and the title of the paper was “Activity of the poly (A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain.”

Normally, MSUT2 works closely with PABPN1 to regulate the biology of Tau in the brain. “And our new study found that inhibiting MSUT2 without affecting PABPN1 could prevent the effects of Tau pathology,” explains Brian Kraemer, who led the study at the University of Washington Medical School.

Earlier, Kraemer and colleagues used C. elegans to conduct research. They found that although nematodes do not have complex cognitive functions, their movement is affected by the accumulation of Tau protein, and knocking out the sut-2 gene of nematodes can reverse the “destructive” of Tau.

The new study carried out such experiments in mice, which evolved at a much smaller distance from humans than from nematodes to humans. The researchers knocked out the MSUT2 gene in mice, which prevented the formation of tau tangles that killed brain cells. It also eases learning and memory problems.

When the researchers looked at autopsy brain samples from patients with Alzheimer’s disease, they found that patients with more severe disease lacked both the MSUT2 protein and its chaperone protein PABPN1. This finding suggests that neurons that lose the MSUT2-PABPN1 protein chaperone may die in a patient’s lifetime.

In addition, mice lacking MSUT2 but with normal PABPN1 strongly resisted abnormal tau accumulation and the resulting brain degeneration. As a result, these researchers have concluded that the key to helping people with an abnormal accumulation of tau is to block MSUT2 while retaining PABPN1 activity.

Participating Jeanna Wheeler believes that the novelty of this research is the discovery of the role of the MSUT2 gene. “If I could use MSUT2 as a drug target in the future, it would be a whole new approach to treating Alzheimer’s disease and other related diseases,” she said.

In recent years, pharmaceutical companies have invested a lot of money around Aβ with little effect. I think the field needs to consider targeting both Aβ and Tau because, in Alzheimer’s disease, these two proteins work together to kill neurons. I hope that our findings can provide clues for other researchers or pharmaceutical companies to carry out related follow-up studies and ultimately achieve the goal of treating or even curing Alzheimer’s disease.


1.Jeanna M. Wheele et al. Activity of the poly(A) binding protein MSUT2 determines susceptibility to pathological tau in the mammalian brain. Science Translational Medicine(2019).

2.Chris R. Guthrie et al. SUT-2 potentiates tau-induced neurotoxicity in Caenorhabditis elegans. Human Molecular Genetics(2009).

source page: New target for Alzheimer’s disease-MSUT2 – BOC Sciences Blog