Role of SLCO1A2 on Oligodendroglial Biology in PSP

Pathway Grant

John Zhou, Yale University

In progressive supranuclear palsy, tau proteins build up abnormally in several types of brain cells, including oligodendrocytes—cells responsible for making myelin, the protective coating that helps nerve signals travel efficiently. Oligodendrocytes are especially affected in PSP, and tau aggregation in oligodendrocytes damage is linked to faster disease progression. Research has also found genetic changes in oligodendrocyte-related genes, including one called SLCO1A2, increase the risk of developing PSP.
The SLCO1A2 gene makes a transporter protein that helps oligodendrocytes take in vital molecules like bile acids and thyroid hormones, both of which are important for cell metabolism and myelin production. Our early studies show that a PSP-associated mutation in SLCO1A2 greatly reduces the protein’s presence on the cell surface and decreases uptake of these molecules by more than half. Without these essential inputs, oligodendrocytes may experience metabolic problems, leading to more tau buildup and myelin loss.

We will study this in two ways:

• Aim 1: We will investigate how the PSP-linked SLCO1A2 mutation affects oligodendrocyte metabolism and tau aggregation. This includes measuring cellular energy production, testing whether the mutation promotes abnormal tau accumulation in laboratory cell models, and whether bile acids/thyroid hormone treatment can protect oligodendrocytes.
• Aim 2: We will examine oligodendrocytes with naturally reduced SLCO1A2 in human PSP brain tissue and stem cell–derived human oligodendrocytes. We will assess whether low SLCO1A2 is associated with poor mitochondrial health, tau buildup, and demyelination, and test how these cells take up bile acids and thyroid hormones. Through these studies, we aim to uncover how SLCO1A2 contributes to oligodendrocyte vulnerability in PSP and to develop new cellular models for testing treatments. This work could identify new ways to protect oligodendrocytes and slow disease progression in PSP.