Postmortem analysis of patients with Alzheimer’s disease, one of nearly 20 neurodegenerative diseases marked by tangled deposits of a protein called tau on neurofibrils, show curious invaginations of nuclear membranes and impaired RNA processing in neurons of the brain. The mechanism that links impaired RNA processing to neuronal death in tauopathies remains unclear.
Earlier studies from a group led by Bess Frost, PhD, professor of neurodegenerative disorders at the University of Texas Health Science Center at San Antonio (UT Health San Antonio) had uncovered heightened RNA export from the nucleus contributes to tau-induced neuronal death through an unknown mechanism.
“We previously found that the nucleus is deformed in brains cells of patients with Alzheimer’s disease. We knew RNA accumulates within invaginations of the nucleus and is toxic to the cell, but we didn’t know why such RNA sequestration would drive cell death,” said Frost.
A new study led by Gabrielle Zuniga, an MD/PhD student in Frost’s laboratory, uses a transgenic fruit fly (Drosophila melanogaster) model of tauopathy that expresses human tau protein, to test whether the piling up of RNA within the invaginations of the nuclear envelope limits the extent to which faulty RNAs are cleared from the cell through nonsense-mediated mRNA decay (NMD), a key RNA quality control mechanism that ousts faulty RNA messages bearing “nonsense” codons that prematurely abort protein synthesis.
“We are focusing on how cells clear faulty RNAs, and how this RNA quality control mechanism goes awry in disease. If these types of RNAs accumulate in a cell and are translated into proteins, bad things can happen,” said Frost.
The new findings from Frost’s team were published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association (“Tau-induced deficits in nonsense-mediated mRNA decay contribute to neurodegeneration”).
The authors said, “We have discovered that tau-induced increase in RNA export leads to a deficit in NMD. We identify tau-induced deficits in RNA quality control as a pharmacologically targetable driver of neurodegeneration that occurs early in the disease process and connects nuclear envelope invagination and RNA to neurodegeneration in the context of tauopathy.”
“Our findings fill an important gap in knowledge through mechanistic insight into how aberrant export of RNA from the nucleus and subsequent sequestration of RNA within nuclear invaginations drive neurodegeneration in Alzheimer’s disease and related tauopathies,” the authors added.
Through genetic manipulations of components of the NMD machinery, Frost’s team showed tau-induced neurotoxicity is altered, suggesting a causal link between deficits in NMD and neurodegeneration in the fly model of tauopathy. The authors found abnormalities in RNA export and the accumulation of transcripts in the invaginations of the nuclear envelop in the fly tauopathy model resulted in reduced NMD.
They also identified a drug that activates NMD and can reduce neuronal death in the transgenic flies expressing human tau. “Based on our findings that deficits in nonsense-mediated RNA decay occur prior to neurodegeneration in a Drosophila model of tauopathy, it is possible that activators of nonsense-mediated RNA decay have disease-modifying potential during the early asymptomatic stages of disease,” said Frost and Zuniga.
Zuniga explained, “Nonsense-mediated mRNA decay is a key step in the process by which genetic information is translated into proteins.” Impairment of this quality-control mechanism results in buildup of RNA and production of abnormal, dysfunctional proteins. Zuniga added, “Changes in RNA quality control occur long before neuronal cell death.”
Prior unsuccessful strategies to treat Alzheimer’s disease and other tauopathies have largely concentrated on removing tau tangles or amyloid beta plaques that constitute classic hallmarks of Alzheimer’s disease.
“Rather than targeting tau deposition, which is late in the disease process, why don’t we stop the pathways that are actually causing the neurons to die? This appears to be one of those pathways, and its discovery is a brilliant piece of detective work by Gabrielle Zuniga, Dr. Frost, and the team,” said Sudha Seshadri, MD, a professor of neurology in the Long School of Medicine and founding director of the Glenn Biggs Institute, who was not involved in the current study. Seshadri and Frost are both investigators of the South Texas Alzheimer’s Disease Research Center, a partnership of UT Health San Antonio and UT Rio Grande Valley.
“Identifying multiple mechanisms underlying tau (and amyloid beta) pathology could result in understanding which patients might benefit from which therapies. For example, a subset of Alzheimer’s disease patients might be responsive to a drug that increases nonsense-mediated mRNA decay,” said Nicolas Musi, MD, professor of medicine at UT Health San Antonio and director of the Sam and Ann Barshop Institute, who also was not involved in the current study.
Frost and Zuniga said, “Our studies pave the way for investigation into dysfunctional RNA quality control as a driver of neurodegeneration in human Alzheimer’s disease and related tauopathies.”
Based on the neuroprotective effect of NMD activators in the Drosophila model of human tauopathy, the team’s future projects will focus on identifying safe compounds that activate NMD and investigate the therapeutic effect of highly selective NMD activators in a vertebrate model of tauopathy.