Overview: Researchers reveal the critical role the p62 gene plays in the selective autophagy of tau oligomers.
Source: National Institutes of Quantum Science and Technology
To maintain cellular homeostasis (i.e., a state of equilibrium), cells undergo selective autophagy, or self-degradation of unwanted proteins. Autophagy receptors regulate this process by mediating the selection of a target protein which is then ‘cleared’.
Tau proteins — which otherwise play an important role in stabilizing and maintaining the internal organization of neurons in the brain — accumulate abnormally in neurons in conditions such as dementia and Alzheimer’s disease.
This build-up of hyperphosphorylated tau proteins (or tau oligomers) causes the formation of neurofibrillary tangles (NFTs) and eventual cell death of neurons in the brains of people with dementia, contributing to the progressive neurodegenerative symptoms of the disease.
While tau proteins can be broken down by selective autophagy, the exact mechanism of how this happens remains a mystery.
In a recent breakthrough, however, a study by scientists at the National Institutes for Quantum Science and Technology in Japan proved the critical role a particular gene — the p62 gene — plays in the selective autophagy of tau oligomers. The team included researcher Maiko Ono and group leader Naruhiko Sahara — both of the Department of Functional Brain Imaging at the National Institutes for Quantum Science and Technology in Japan.
Their paper, published in Aging cellwas made available online on June 5, 2022.
Previous studies have reported that the abnormal accumulation of the tau proteins can be selectively suppressed by autophagy pathways, via the p62 receptor protein (which is a selective autophagy receptor protein).
Maiko Ono says, “The ubiquitin-binding capacity of this protein aids in the identification of toxic protein aggregates (such as tau oligomers), which can then be broken down by cellular processes and organelles.”
However, the novelty of this study lay in the demonstration of the “neuroprotective” role of p62 in a living model, which had never been done before. So, how did the researchers achieve this? They used mouse models of dementia. The p62 gene was deleted (or disabled) in one group of these mice, so they did not express p62 receptor proteins.
When studying the brains of these mice using immunostaining and comparative biochemical analyses, an interesting picture was revealed. Neurotoxic tau protein aggregates were found in the hippocampus – the area of the brain associated with memory – and brainstem – the center that coordinates the body’s breathing, heart rate, blood pressure and other voluntary processes – of p62 knockout (KO) mice.
When we consider this together with the symptoms of dementia, including memory loss, confusion and mood swings, these findings make a lot of sense.
MRI scans revealed that the hippocampus of p62 KO mice was degenerated (atrophic) and inflamed. A postmortem assessment of their brains revealed a greater loss of neurons in their hippocampus.
Further immunofluorescence studies showed that the abnormal aggregates of tau species can induce cytotoxicity leading to inflammation and cell death of neurons in p62 KO mice. In particular, oligomeric tau accumulated more in the brains of p62 KO mice.
Overall, the findings of this study prove that by eliminating and thus preventing the aggregation of oligomeric tau species in the brain, p62 played a neuroprotective role in models of dementia.
At a time when researchers around the world are trying to develop drugs for dementia and other related neurodegenerative disorders, the findings of this study will be instrumental in providing evidence for the accurate targeting of tau oligomers.
The world population of aging people is increasing every year; therefore, the need to develop methods to slow the onset and progression of various neurodegenerative diseases is also increasing.
This research offers a positive step towards meeting that need.
About this genetics and neuroscience research news
Author: press office
Source: National Institutes of Quantum Science and Technology
Contact: Press Agency – National Institutes of Quantum Science and Technology
Image: Image is credited to National Institutes for Quantum Science and Technology
Original research: Open access.
†Central role for p62/SQSTM1 in the elimination of toxic tau species in a mouse model of tauopathyby Maiko Ono et al. Aging cell
Central role for p62/SQSTM1 in the elimination of toxic tau species in a mouse model of tauopathy
Intracellular accumulation of filamentous tau aggregates with progressive neuronal loss is a common feature of tauopathies. While the neurodegenerative mechanism of tau-associated pathology remains unclear, molecular elements capable of degrading and/or sequestering neurotoxic tau species may suppress neurodegenerative progression.
Here we provide evidence that p62/SQSTM1, a ubiquitous cargo receptor for selective autophagy, is protective against neuronal death and neuroinflammation caused by abnormal tau accumulation.
P301S mutant tau transgenic mice (line PS19) showed accumulation of neurofibrillary tangles with p62 localization mostly in the brainstem, but neuronal loss with few neurofibrillary tangles in the hippocampus.
In the hippocampus of PS19 mice, the p62 level was lower compared to the brainstem, and punctate accumulation of phosphorylated tau unaccompanied by p62 co-localization was observed. In PS19 mice deficient in p62 (PS19/p62-KO), increased accumulation of phosphorylated tau, acceleration of neuronal loss and exacerbation of neuroinflammation were observed in the hippocampus compared to PS19 mice. In addition, an increase in abnormal tau and neuroinflammation was observed in the brainstem of PS19/p62-KO.
Immunostaining and dot-blot analysis with an antibody that selectively recognizes tau dimers and higher-order oligomers revealed that oligomeric tau species in PS19/p62-KO mice accumulated significantly compared to PS19 mice, suggesting that p62 is required to eliminate disease-related oligomeric tau species.
Our findings indicated that p62 exerts neuroprotection against tau pathologies by eliminating neurotoxic tau species, suggesting that the manipulative p62 and selective autophagy may provide an intrinsic therapy for the treatment of tauopathy.