RNA Molecule Appears to Regulate Tau Levels in Brain, Study Says

The production of tau — a protein that forms toxic aggregates in Parkinson’s disease — in the brain is tightly regulated by a small, regulatory RNA molecule called MAPT-AS1, a study reports.

Notably, increasing MAPT-AS1 production in the brains of mice significantly reduced tau levels, suggesting that similar approaches might slow disease progression in tau-related neurodegenerative diseases, such as Parkinson’s, Alzheimer’s disease, corticobasal degeneration, and progressive supranuclear palsy.

MAPT-AS1 was also found to belong to a family of similar molecules that regulate the production of other toxic proteins that accumulate in Parkinson’s and other neurodegenerative diseases.

“This means we may have found the key to regulating the production of a whole range of proteins involved in brain function and the development of these devastating conditions,”  Rohan de Silva, PhD, the study’s senior author at University College London’s Queen Square Institute of Neurology, said in a university press release.

“It’s early days but we hope that these exciting new insights will lead to the development of [treatments] that can keep tau and other proteins under control, and that these therapies could be life-changing for degenerative brain conditions that as yet, have no treatments to halt, let alone slow their progression,” de Silva added.

The study, “MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration,” was published in the journal Nature.

“Tau is emerging as one of the key determinants of different rates of progression in Parkinson’s so understanding how this protein is regulated may be vital to finding better treatments and a cure” said David Dexter, PhD, the associate director of research at Parkinson’s UK, which partly funded the study.

A team led by de Silva, along with colleagues at other European institutions, provided the first conclusive evidence that tau production is tightly regulated by an antisense long non-coding RNA (lncRNA), called MAPT-AS1.

LncRNAs are complementary molecules to a gene’s messenger RNA (mRNA) — the intermediate molecule derived from DNA that guides protein production — preventing its use in generating the protein coded by that gene.

As such, the production of certain proteins may require a fine-tuned balance between mRNA and opposing lncRNAs molecules, and a dysregulation of either molecule can lead to disease-causing processes.

The researchers showed that increasing MAPT-AS1 levels significantly lowered tau protein levels in cells grown in the lab, while suppressing MAPT-AS1 significantly increased those levels. Both changes came without affecting mRNA levels of MAPT, the gene that provides the instructions to produce the tau protein.

Similar effects were observed in mice with age-dependent, tau-related neurodegeneration. An induced boost in MAPT-AS1 levels in the brains of these mice significantly dropped tau levels by about 50%.

Notably, MAPT-AS1 was previously shown to be at lower levels in the brains of Parkinson’s patients than in healthy individuals. In addition, people with a particular form of the MAPT gene, called H1, are known to produce more tau and to at a higher risk of Parkinson’s, corticobasal degeneration, and progressive supranuclear palsy, de Silva noted.

Together, these findings suggest that a dysregulation of MAPT-AS1 levels may be behind excessive tau production and the consequent formation of toxic clumps.

“If we can find a way to boost the levels of this lncRNA, we might be able to reduce the production of tau protein which could help to slow or stop the damage to cells inside the brain,” said de Silva, adding that that’s exactly what he and his team are working on.

A gene therapy the team is developing to deliver MAPT-AS1 to brain cells is under testing in mice and other animal models.

“If it’s successful, we hope to take this approach forward to be developed as a new therapy that can one day be tested in people,” de Silva said.

The researchers also identified antisense lncRNAs similar to MAPT-AS1 that appear to regulate the production of other proteins that accumulate to toxic levels in neurodegenerative diseases, such as alpha-synuclein in Parkinson’s and amyloid-beta in Alzheimer’s.

“It’s especially exciting to see that similar mechanisms may be involved in controlling the production of many other key proteins implicated in other neurological conditions, as it suggests strategies targeting these mechanisms could be effective across many conditions,” Dexter said.