Groundbreaking study demonstrates central role of protein p62 in suppressing neurodegenerative disorders via selective autophagy

Neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease are defined by a pathogenic accumulation of toxic proteins in the brain. Now, however, scientists from the National Institutes for Quantum Science and Technology have established that the protein p62, which is involved in the breakdown of cellular proteins, can prevent the accumulation of toxic oligomeric tau species in the brains of mice, proving – for the first time – – the “neuroprotective” function of p62 in a living model.

In order to maintain cellular homeostasis (i.e. a state of balance), cells undergo selective autophagy or self-degradation of unwanted proteins. Autophagy receptors control this process by intervening in the selection of a target protein which is then ‘eliminated’.

Tau proteins – which otherwise play an important role in stabilizing and maintaining the internal organization of neurons in the brain – accumulate abnormally inside neurons in conditions such as dementia and brain disease. Alzheimers. This accumulation 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. Now, while tau proteins can be degraded by selective autophagy, the exact mechanism of how this happens remains a mystery.

In a recent breakthrough, however, a study by scientists from the National Institutes for Quantum Science and Technology in Japan proved the critical role played by a certain gene – the p62 gene — in selective autophagy of tau oligomers. The team included researcher Maiko Ono and group leader Naruhiko Sahara, both from the Department of Functional Brain Imaging at the National Institutes for Quantum Science and Technology in Japan. Their article, published in aging cellwent live on June 5, 2022.

Previous studies have reported that abnormal tau accumulation can be selectively suppressed through autophagy pathways, via the p62 receptor protein (which is an autophagy-selective receptor protein). According to Maiko Ono, “The ubiquitin-binding ability of this protein helps identify toxic protein aggregates (like tau oligomers), which can then be degraded by cellular processes and organelles. »

The novelty of this study, however, lies 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 had been deleted (or knocked out) in one group of these mice, so they did not express the p62 receptor proteins.

By studying the brains of these mice using immunostaining and comparative biochemical analyses, an interesting picture was revealed. Aggregates of neurotoxic tau proteins have been found in the hippocampus – the area of ​​the brain associated with memory – and the brainstem – the center that coordinates breathing, heart rate, blood pressure and other voluntary body processes – of p62 knockout (KO) mice. When we consider this along with the symptoms of dementia, which include memory loss, confusion, and mood changes, these findings make a lot of sense.

MRI scans revealed that the hippocampus of p62 KO mice was degenerated (atrophied) and inflamed. A post-mortem evaluation of their brains revealed greater loss of neurons in their hippocampus. Further immunofluorescence studies have shown that abnormal aggregates of tau species can cause cytotoxicity leading to inflammation and cell death of neurons in p62 KO mice. Oligomeric tau, in particular, accumulated more in the brains of p62 KO mice.

Taken together, the results of this study provide evidence that by eliminating and, therefore, 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 results of this study will be of great importance in providing evidence for the precise targeting of tau oligomers. The global population of aging humans is growing every year; therefore, the need to develop methods to slow the onset and progression of various neurodegenerative diseases is also growing. This study is a positive step towards meeting that need.

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