Understanding USP9

LUXEMBOURG CITY, Luxembourg—In the effort to find treatment options for Alzheimer’s disease, many researchers have set their sights on addressing some of the hallmarks of the disease, such as amyloid beta plaques. But now there might be a new genetic target, thanks to scientists from the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg. A team led by Dr. Enrico Glaab has found that the USP9 gene has an indirect influence on the tau protein, which is thought to be a key culprit in the disease’s onset. Their results were published in Molecular Neurobiology.

Alzheimer’s disease is a neurodegenerative condition in which neurons and synapses in the brain are progressively damaged and lost. The damage is due in part to plaque deposits formed of amyloid beta and the accumulation of tau proteins into neurofibrillary “tangles” that disrupt brain cell function. Some 35 million people worldwide are thought to have Alzheimer’s disease, and that number is expected to reach 65 million by 2030 and more than 100 million by 2050.

The team came across USP9—or ubiquitin-specific peptidase 9—when looking for molecular differences that could explain why women have a higher risk of developing Alzheimer’s than men do. The researchers analyzed thousands of data series on post-mortem samples from the brains of roughly 650 people of both sexes, some who had had Alzheimer’s disease and some who hadn’t. USP9 is known to influence the activity of a gene that encodes the microtubule associated protein tau (MAPT), which is suspected of playing a role in Alzheimer’s disease onset.

“USP9 is a sex-linked gene with a Y-chromosomal (USP9Y) and an X-chromosomal form (USP9X), and the total concentrations of USP9 in the human brain (USP9X + USP9Y combined) differ significantly between the genders, both in post-mortem brains of individuals without any known brain disorder and in Alzheimer’s disease patients (in particular in males, we also observed significant USP9 activity changes in patients compared to controls),” explains Glaab, head of the research group Biomedical Data Science at LCSB. “Although we cannot exclude that the X- and Y-form of the USP9 gene also have partly different functions, our previous experiments rather suggest that the differences in the activity of USP9 between the genders mainly result from total concentration differences, rather than from diverse protein functionality of the X- and Y-form.”

Glaab and his colleagues from other LCSB workgroups studied USP9 in cell cultures and zebrafish experiments to see what effects knocking the gene down would have. What they found, according to Glaab, was that “USP9 knockdown significantly reduces the activity of the tau gene in both models.” The team then developed a computer model to combine the measured data with known regulatory information to try and map the molecular signal chain that connects USP9 and MAPT, and found that proteins that had previously been highlighted as potential drug targets are influenced by USP9. Therefore, if USP9 could be effectively manipulated, it could affect multiple tau regulators for greater impact.

“The known target proteins of USP9 include MARK4, a kinase that phosphorylates the Alzheimer’s disease associated protein tau, and the transcription factor SMAD4, which can influence the gene expression of tau via the protein BACH1,” Glaab tells DDNews. “Recently, USP9 has also been shown to interact with tau in a generic mapping study of tau interaction partners. Direct evidence that USP9 can prevent the degradation of tau via ubiquitin removal is not yet available; however, we could show in different model systems that the knockdown of USP9 results in a significantly altered gene expression of tau. While our work mainly focuses on the associations between USP9 and tau, alterations in USP9 activity certainly also influence other cellular mechanisms via its target proteins, but this remains to be investigated in detail.”

“To improve our understanding of the regulatory network around USP9, and the changes occurring in USP9 activity over time in Alzheimer’s disease, we are now analyzing USP9 in an Alzheimer’s disease mouse model with injected amyloid-beta oligomers and in wild-type mice at different ages,” Glaab says of the team’s next steps for this work.