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Alzheimer’s Tau Protein Interacts with RNA to Induce Neurodegeneration

Misfolding and aggregation of the microtubule-associated protein tau (MAPT) are core features of Alzheimer’s disease (AD). As the neurons get sick, they show characteristic changes, such as the accumulation of neurofibrillary tangles, which are composed of misfolded tau protein. The accumulation of tau is closely correlated with cognitive decline in AD patients.

Yet, neurofibrillary tangles are just one piece of AD pathology. Scientists have been striving to understand how nerve cell injury gives rise to neurofibrillary tangles, which could be important to know to develop the best drugs and diagnostics for AD. Now, researchers from the Boston University School of Medicine (BUSM) have discovered a new type of molecular pathology that accumulates in the nerves cells of patients with AD.

Findings from the new study were published recently in Molecular Cell through an article titled, “Interaction of tau with HNRNPA2B1 and N6-methyladenosine RNA mediates the progression of tauopathy.” Understanding the role of tau protein in AD can lead to new ways to diagnose it as well as the creation of medicines now in clinical trials to treat it.

“We have found that as the injured nerve cells accumulate misfolded tau protein, they put a tag on RNA. The amount of a tagged RNA called N6-Methyladenosine (m6A) increases about four-fold over the course of the disease,” explained senior study investigator Benjamin Wolozin, MD, PhD, a professor of pharmacology & experimental therapeutics at BUSM.

Wolozin and his group further showed that inhibiting the RNA-tagging pathway protects against nerve cell injury (neurodegeneration) associated with the accumulation of misfolded tau. This important result raises the possibility that blocking the RNA-tagging pathway might provide a novel approach to treat AD.

“We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis,” the authors wrote. “Proteomic analysis identifies HNRNPA2B1 as a principal target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues.”

The research team then went on to investigate why these RNA tags accumulate with disease. The group used optogenetics (genes for light-sensitive proteins are introduced into specific types of brain cells in order to monitor and control their activity precisely using light signals) combined with protein analysis to discover that misfolded tau specifically binds RNA that has these tags and does so with the help of another RNA binding protein, termed HNRNPA2B1 (which is also linked to a type of brain degeneration termed amyotrophic lateral sclerosis).

“Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine (m6A) modified RNA transcripts,” the authors penned. “Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m6A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m6A and the m6A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice.”

The BUSM team showed that binding of misfolded tau or HNRNPA2B1 is necessary for the entire complex to exert biological actions—genetically lowering either species blocks neurodegeneration and also reduces the amount of tagged RNA that accumulates. The team hypothesizes that this complex is designed to respond to injury but that in AD, the response becomes hyperactive, persistent, and therefore harmful.

“This work opens up a new avenue that investigators can use to explore the process of AD and in the process perhaps develop new approaches to treat the disease,” Wolozin concluded.

The post Alzheimer’s Tau Protein Interacts with RNA to Induce Neurodegeneration appeared first on GEN – Genetic Engineering and Biotechnology News.

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