Studies by researchers at University of South Florida Health (USF Health) Morsani College of Medicine have found that a protein known as -arrestin2 increases the accumulation of the neurotoxic tau tangles that cause several forms of dementia, by interfering with the process that cells use to remove excess tau from the brain. The studies demonstrated that an oligomerized form of -arrestin2, but not monomeric -arrestin2, disrupted the process of autophagy, which would normally act to help rid cells of malformed proteins like disease-causing tau.
Encouragingly, in vivo studies showed that blocking -arrestin2 oligomerization suppressed disease-causing tau in a mouse model that develops a form of human frontotemporal lobar degeneration (FTLD) with dementia, a form of neurodegeneration that is characterized by tau accumulation and the formation of neurofibrillary tangles. Our research could lead to a new strategy to block tau pathology in FTLD, Alzheimers disease, and other related dementias, which ultimately destroys cognitive abilities such as reasoning, behavior, language, and memory, said Jung-A (Alexa) Woo, PhD, an assistant professor of molecular pharmacology and physiology and an investigator at the USF Health Byrd Alzheimers Center. Woo is lead author of the teams published paper in theProceedings of the National Academy of Sciences(PNAS), which is titled, -arrestin2 oligomers impair the clearance of pathological tau and increase tau aggregates.
FTLD, which is also called frontotemporal dementia, is second only to Alzheimers disease (AD) as the leading cause of dementia. This aggressive form of dementia is typically earlier onset, in people aged 4565, and is characterized by atrophy of the front or side regions of the brain, or both. The two primary hallmarks of Alzheimers disease are clumps of amyloid-beta (A) protein fragments known as amyloid plaques, and the tangles of tau protein. Abnormal accumulations of both proteins are needed to drive the death neurons in Alzheimers, although recent research suggests that tau accumulation appears to be required for the toxic effects of A in AD, and correlates better with cognitive dysfunction than A. Indeed, tauopathy correlates significantly better than A with cognitive deficits in AD, the team noted, and drugs targeting A have been disappointing as a treatment.
Like Alzheimers disease, FTLD displays an accumulation of tau, which results in the formation of tau-laden neurofibrillary tangles that destroy synaptic communication between neurons, eventually killing the brain cells. There is no specific treatment or cure for FTLD. However, in contrast with AD, A aggregation is absent in the FTLD brain, in which the key feature of neurodegeneration appears to be the excessive tau accumulation, known as tauopathy. In contrast to AD, where amyloid is an integral part of the tangle, there is no accumulation of A in FTLD neurons , the authors noted.
Previous studies have pointed to an association between G protein-coupled receptors (GPCRs) and AD pathogenesis, and have linked the activation of several, diverse GPCRs with A and/or tau pathogenesis in animal models. While it isnt clear how these very different GPCRs can impact on A and tau pathogenesis, and neurodegeneration in AD, one potential commonality among the receptors is their interaction with arrestins, the researchers noted. Interestingly, previous studies have shown that one of the family of -arrestin proteins known as -arrestin2, is increased in AD brains, and genetic studies have shown that endogenous -arrestin2 promotes A production and deposition, linking -arrestin2 to A pathogenesis. Despite this evidence, the authors acknowledged, prior to the current work, however, it was not known whether, or how, -arrestin2 pathogenically impinges on tauopathy and neurodegeneration in AD, or in FTLD where there is no accumulation of A. As Woo commented, Studying FTLD gave us that window to study a key feature of both types of dementias, without the confusion of any A component.
-arrestin2 in its monomeric form is mostly known for its ability to regulate receptors, but -arrestin2 can also form multiple interconnecting units, called oligomers, and the function of -arrestin2 oligomers is not well understood. While the monomeric form was the basis for the laboratorys initial studies examining tau and its relationship with neurotransmission and receptors, Woo said, we soon became transfixed on these oligomers of -arrestin2.
The teams studies confirmed the presence of elevated -arrestin2 levels, both in cells from the brains of TFLD-tau patients, and in a mouse model. This model expresses disease-associated tau in neurons, and displays FTLD-like pathophysiology and behavior and, like FTLD in humans, doesnt accumulate A.
The researchers also found that -arrestin2 acts to increase tau stability via scaffolding potein:protein interactions. Their results indicated that when -arrestin2 is overexpressed, tau levels also increase, suggesting a maladaptive feedback cycle that exacerbates disease-causing tau. As the authors commented, the data suggested that increased tau increases -arrestin2, which in turn acts to further potentiate tau-mediated events by stabilizing the protein, thus indicative of a vicious positive pathogenic feedback cycle.
To determine the effects of reducing -arrestin2 levels, the team crossed a mouse model of early tauopathy with genetically modified mice in which the -arrestin2 gene was inactivated. They demonstrated that genetic knockdown of -arrestin2 also reduced tauopathy, synaptic dysfunction, and the loss of nerve cells and their connections in the brain. Importantly, experiments confirmed that it was oligomerized -arrestin2, and not the proteins monomeric form, which was associated with increased tau. By blocking -arrestin2 molecules from binding together to create oligomerized forms of the protein, the investigators demonstrated that pathogenic tau significantly decreased when only monomeric -arrestin2, which does bind to receptors, was present.
Further experiments indicated that oligomerized -arrestin2 increases tau by impeding the ability of cargo protein p62 to help selectively degrade excess tau in the brain. In effect, this reduces the efficiency of the autophagy process that would otherwise clear toxic tau. The resulting accumulation of tau clogs up the neurons. Blocking -arrestin2 oligomerization also suppressed disease-causing tau in the mouse model that develops human tauopathy with signs of dementia.
Specifically, our results indicate that -arrestin2 oligomers increase tau levels by blocking the self-interaction of p62, an initial step essential in p62-mediated autophagy flux, the team commented. Genetic reduction or ablation of -arrestin2 significantly decreased sarkosyl-insoluble tau and mitigated tauopathy in vivo. Furthermore, -arrestin2 mutants incapable of forming oligomersactually reduced insoluble tau.
It has always been puzzling why the brain cannot clear accumulating tau, said Stephen B. Liggett, MD, senior author and professor of medicine and medical engineering at the USF Health Morsani College of Medicine. It appears that an incidental interaction between -arrestin2 and the tau clearance mechanism occurs, leading to these dementias. -arrestin2 itself is not harmful, but this unanticipated interplay appears to be the basis for this mystery We also noted that decreasing -arrestin2 by gene therapy had no apparent side effects, but such a reduction was enough to open the tau clearance mechanism to full throttle, erasing the tau tangles like an eraser. This is something the field has been looking foran intervention that does no harm and reverses the disease.
The results point to a potential therapeutic strategy for tauopathies such as FTLD, based on partial inhibition of -arrestin2 oligomerization. For gene therapy of human FTLD-tau, mutants with a somewhat decreased capacity for such inhibition might be desirable, so that some levels of the oligomer are present to carry out other functions Similarly, small molecule inhibitors of -arrestin2 oligomerization, given for treatment or prevention of FTLD-tau, could be designed to spare complete loss of the oligomer in the cell, they suggested. Based on our findings, the effects of inhibiting -arrestin2 oligomerization would be expected to not only inhibit the development of new tau tangles, but also to clear existing tau accumulations due to this mechanism of enhancing tau clearance.
This treatment strategy could be both preventative for at-risk individuals and those with only mild cognitive impairment, and therapeutic in patients with evident FTLD-tau, by decreasing existing tau tangles. Beyond tauopathy, it is conceivable that this strategy could also prove to be beneficial in other neurodegenerative diseases bearing proteinopathies that are cleared via p62, the scientists concluded.
This study identifies beta-arrestin2 as a key culprit in the progressive accumulation of tau in brains of dementia patients, added co-author David Kang, PhD, professor of molecular medicine and director of basic research for the Byrd Alzheimers Center. It also clearly illustrates an innovative proof-of-concept strategy to therapeutically reduce pathological tau by specifically targeting beta-arrestin oligomerization.
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Protein that Prevents Tau Clearance Linked to AD and Other Tau Tangle Proteinopathies - Clinical OMICs News
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