In today's research materials, scientists report on the discovery of a maladaptive response to the presence of tau aggregates in brain cells, one that makes the situation worse than it would otherwise be. Tau is one of a small number of proteins that can become altered in a way that ensures other molecules of the same protein also alter. They join together and precipitate into solid structures, known as neurofibrillary tangles in the case of tau, accompanied by a halo of disrupted biochemistry that is harmful to cell and tissue function. This spreads, seeding dysfunction as it moves from cell to cell, or throughout a tissue between cells.
Cells do attempt to fight back against the spread of broken proteins and their aggregates. Multiple mechanisms allow cells to ingest and break down aggregates present between cells, and aggregates inside cells are also fed into the same recycling machinery. It is perhaps the case that neurodegenerative conditions are age-related in large part because the machinery of autophagy, an important recycling mechanism in cells, degrades with age. The efforts to reduce molecular waste such as protein aggregates falter.
Here, researchers have found that an oligomerized form of β-arrestin-2 acts to interfere with the processes of autophagy as they attempt to remove aggregated tau protein. Normally cells recycle unwanted protein machinery and damaged structures by delivering these materials to a lysosome to be broken down, but an important component of autophagy is inhibited by oligomerized β-arrestin-2. Interestingly, preventing β-arrestin-2 from adopting this unhelpful form reduces tau pathology in mouse models of tauopathy with no apparent side-effects.
Researchers have discovered that a form of the protein comprised of multiple β-arrestin-2 molecules, known as oligomerized β-arrestin-2, disrupts the protective clearance process normally ridding cells of malformed proteins like disease-causing tau. Monomeric β-arrestin-2, the protein's single-molecule form, does not impair this cellular toxic waste disposal process known as autophagy. The study focused on frontotemporal lobar degeneration (FTLD), also called frontotemporal dementia - second only to Alzheimer's disease as the leading cause of dementia. This aggressive, typically earlier onset dementia (ages 45-65) is characterized by atrophy of the front or side regions of the brain, or both. Like Alzheimer's disease, FTLD displays an accumulation of tau, and has no specific treatment or cure.
Both in cells and in mice with elevated tau, β-arrestin-2 levels are increased. Furthermore, when β-arrestin-2 is overexpressed, tau levels increase, suggesting a maladaptive feedback cycle that exacerbates disease-causing tau. Genetically reducing β-arrestin-2 lessens tauopathy, synaptic dysfunction, and the loss of nerve cells and their connections in the brain. Oligomerized β-arrestin-2 - but not the protein's monomeric form - increases tau.
Oligomerized β-arrestin-2 increases tau by impeding the ability of cargo protein p62 to help selectively degrade excess tau in the brain. In essence, this reduces the efficiency of the autophagy process needed to clear toxic tau, so tau "clogs up" the neurons. Blocking of β-arrestin-2 oligomerization suppresses disease-causing tau in a mouse model that develops human tauopathy with signs of dementia. "We also noted that decreasing β-arrestin-2 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. This is something the field has been looking for - an intervention that does no harm and reverses the disease."
Multiple G protein-coupled receptors (GPCRs) are targets in the treatment of dementia, and the arrestins are common to their signaling. β-Arrestin2 was significantly increased in brains of patients with frontotemporal lobar degeneration (FTLD-tau), a disease second to Alzheimer's as a cause of dementia. Genetic loss and overexpression experiments using genetically encoded reporters and defined mutant constructs in vitro, and in cell lines, primary neurons, and tau P301S mice crossed with β-arrestin2 knockout mice, show that β-arrestin2 stabilizes pathogenic tau and promotes tau aggregation. Cell and mouse models of FTLD showed this to be maladaptive, fueling a positive feedback cycle of enhanced neuronal tau via non-GPCR mechanisms.
Genetic ablation of β-arrestin2 markedly ablates tau pathology and rescues synaptic plasticity defects in tau P301S transgenic mice. Atomic force microscopy and cellular studies revealed that oligomerized, but not monomeric, β-arrestin2 increases tau by inhibiting self-interaction of the autophagy cargo receptor p62/SQSTM1, impeding p62 autophagy flux. Hence, reduction of oligomerized β-arrestin2 with virus encoding β-arrestin2 mutants acting as dominant-negatives markedly reduces tau-laden neurofibrillary tangles in FTLD mice in vivo. Reducing β-arrestin2 oligomeric status represents a new strategy to alleviate tau pathology in FTLD and related tauopathies.