Characterization of Tau and Its Pathology in Oligodendrocytes Derived from Induced Pluripotent Stem Cells from Patients with PSP-like Phenotype

Principal Investigator: Dr. Ragnhildur Thora Karadottir
University of Cambridge, UK

 

C0126039 Ragnhildur Karadottir - Researcher Meetin

Examining the role of oligodendrocytes (glial cells creating the myelin sheath) in PSP pathology using stem cells. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are characterized by the presence of tau protein aggregates in neurons and glial cells.

Although the disorder is usually sporadic in its occurance in the general population, the tau pathology observed in the brain of PSP patients resembles that present in some familial cases with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T) caused by mutations in the MAPT gene, thus supporting the involvement of tau in PSP pathogenesis. White matter pathology and oligodendroglial lesions are specifically prominent in sporadic PSP, CBD and some cases of FTDP-17T, but their relevance for disease pathogenesis is not known.

Furthermore, the genome wide association study (GWAS) carried out in PSP patients has identified several genes as risk factors for the disease, including myelin structural proteins, arguing for a possible role of oligodendrocytes, the myelin producing cells, in disease development. However, it is currently unknown how tau modifications affect oligodendrocyte function, and it is even unclear whether human oligodendrocytes express tau or take it up from surrounding neurons. This study has produced neurons derived from skin cells of patients with MAPT mutations that have a tau pathology similar to that found in PSP cases.

The aim of the present application is to generate oligodendrocytes from induced pluripotent stem cells from the same patients with MAPT mutations as well as control subjects from whom neurons have been generated. In these human oligodendrocytes we will investigate the expression and possible modifications of tau protein and if any relationship exists with neuronal tau alterations.

This study will help in understanding whether oligodendrocytes are key players in the development of pathology in PSP thus paving the way to a new mechanism-based therapeutic avenue.

Results 

Progressive supranuclear palsy (PSP) is characterized by the presence of tau protein aggregates in both neurons and oligodendrocytes. White matter pathology and oligodendroglial lesions are specifically prominent in sporadic PSP but their relevance for disease pathogenesis is yet unknown. Furthermore, the genome-wide association study (GWAS) carried out in PSP patients has identified several risk factors for the disease, including Myelin structural proteins, arguing for a possible role of oligodendrocytes-the Myelin producing cells-in disease development. However, it is currently unknown how tau modifications affect oligodendrocyte function, and it is even unclear whether human oligodendrocytes express tau or take it up from surrounding neurons. Thanks to the support of CurePSP we have produced human oligodendrocytes derived from skin cells of healthy individuals and patients with tau mutations that have pathology similar to that found in PSP cases. We showed for the first time that both human and rat oligodendrocytes physiologically express tau mRNA and tau protein isoforms that exist in the human adult brain. Moreover, we showed that the expression of mutated tau in human oligodendrocytes does not alter ion-channel or Glutamate receptor expression levels in the cells derived from patients with PSP-like pathology. Although the basic membrane properties of tau-mutated human oligodendrocytes remain unaltered, evidence suggests that the Myelin structure and integrity is disrupted in human PSP-like oligodendrocytes. This study has showed for the first time that human oligodendrocytes express tau protein and that oligodendrocytes might be an important player in the development of PSP, paving the way to a new therapeutic avenue focusing on the white matter.