Neurodegenerative Diseases Treatment Strategies Revealed

The Tanz Centre for Research in Neurodegenerative Diseases at the University of Toronto used novel techniques to determine which subtypes of brain cells express genetic material that produces tau, a key protein involved in the development of the neurodegenerative disease progressive supranuclear palsy (PSP).

According to the study, which was just published in the journal Acta Neuropathologica, a two-pronged strategy to treatment that targets two important pathways in illness progression may be more effective than existing treatments.

“This study uses a novel methodology to show that the glial cells – the supporting brain tissue – can produce tau themselves and become diseased without taking up tau from nerve cells. Therefore, glial cells are more important in disease pathogenesis than previously assumed,” says Gabor Kovacs, investigator at the Tanz Centre and a professor in the Temerty Faculty of Medicine’s department of laboratory medicine and pathobiology.

“This study also shows that RNA expression of tau, thus the production of tau, is preserved during disease and providing a continuous supply of tau, which should be kept in mind in therapy development.”

The accumulation of misfolded tau protein in neurons and their supporting cells is a typical hallmark of neurodegenerative diseases such as PSP and Alzheimer’s disease, limiting their function.

Researchers have long argued which brain cells express the tau-coding gene MAPT. For decades, it was widely assumed that neurons express MAPT RNA while glial cells do not.

According to Shelley Forrest, a neuropathologist and research associate with Kovacs’ team, neuropathologists have detected tau clumps in glial cells, but there was no firm proof as to where they were coming from.

“In these neurodegenerative diseases, we find pathological tau aggregates in the glia, so there’s always been active debate on why tau pathology accumulates in glia, and whether it’s produced by neurons and taken up by glia or whether glia can make it themselves independently,” says Forrest.

The research team, which comprised collaborators from Australia and Dubai, evaluated brain tissue samples from three PSP patients and three control patients. Having access to these post-mortem patient samples – which Forrest characterizes as “the most generous gift anyone can give” – allowed the researchers to get a more complete and realistic picture of RNA expression in distinct brain cell types than they would have gotten from animal models or cell cultures.

The researchers employed novel RNAscope technology to view RNA molecules under the microscope, as well as single nucleus RNA sequencing, to map RNA expression in different brain areas and brain cell types. The combination of patient samples and new technologies allowed the researchers to see for the first time where MAPT RNA is expressed in the brain.

The researchers discovered that the amount of MAPT RNA expressed by different brain areas and brain cells varies. They also discovered that glial cells indeed express MAPT RNA, which is the first substantial evidence of its presence in these cells. This suggests that glial cells not only take up misfolded tau produced by neurons, but also manufacture it.

“We’ve long had this suspicion, but now we’ve been able to get the evidence to demonstrate that this is the case,” says Forrest. “How and why tau accumulates in glia in PSP is not entirely clear, but our study highlights two novel mechanistic pathways for the cell-to-cell transmission of misfolded tau and accumulation in the brain, which is an exciting result.”

The findings indicate that a two-pronged approach to therapy – targeting both misfolded tau protein and MAPT RNA expression – may be the most effective technique for treating PSP and other comparable disorders.

“Because we’re proposing two different pathways for the pathogenesis of the disease, if you only focus on one, you’re just getting half the picture,” says Forrest. “If you block one pathway, it will just proceed with the other pathway. You’ve got to block both.”

Kovacs’ team will now apply similar methods to investigate the same question in other neurodegenerative disorders. They will also follow up on these findings to better understand RNA expression in different brain regions.

“Our team is one of the first to use these techniques in neurodegenerative-diseased human brain samples. We will now expand this examination to other diseased proteins and map how changes in the tau RNA expression affect expression of crucial genes at the cellular level, focusing on glial cells,” Kovacs says.

“Ultimately, this work will inform basic researchers to focus on glial cells – not just neurons – when trying to unravel the pathogenesis of PSP, and will inform therapy developers to not only remove misfolded tau as they currently do, but also decrease production of normal tau using RNA-based therapies.”

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