In order to maintain cellular homeostasis (i.e., a state of equilibrium), cells undergo selective autophagy or self-degradation of unwanted proteins. Autophagy receptors control this process, by mediating the selection of a target protein that is then “cleared.”
Tau proteins—which otherwise play an important role in stabilizing and maintaining the internal organization of neurons in the brain—abnormally accumulate inside neurons in conditions like dementia and Alzheimer’s disease. This build-up of hyper-phosphorylated 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 disease’s progressive neurodegenerative symptoms. Now, while tau proteins can be degraded by selective autophagy, the exact mechanism of how this occurs remains a mystery.
In a recent breakthrough, however, a study done by scientists proved the critical role played by a certain gene—the p62 gene—in the selective autophagy of tau oligomers. The team published their work in the journal Aging cell.
Previous studies have reported that the abnormal accumulation of the tau proteins may be selectively suppressed by autophagy pathways, through the p62 receptor protein (which is a selective autophagy receptor protein). Says the author, “This protein’s ubiquitin-binding ability helps in the identification of toxic protein aggregates (like tau oligomers), which can then be degraded by cellular processes and organelles.”
This study’s novelty, however, lay in the demonstration of p62’s “neuroprotective” role 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 p62 receptor proteins.
On 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, heartbeat, blood pressure, and other voluntary 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 postmortem assessment of their brains revealed a greater loss of neurons in their hippocampus. Further immunofluorescent studies showed that the abnormal tau species aggregates can cause cytotoxicity leading to inflammation and cell death of neurons in p62 KO mice. Oligomeric tau, specifically, accumulated more in the brains of p62 KO mice.
Overall, the findings of this study prove that by eliminating and, hence, preventing the aggregation of oligomeric tau species in the brain, p62 played a neuroprotective role in models of dementia.
At a time when researchers across the word are trying to develop drugs for dementia and other related neurodegenerative disorders, the findings of this study will be of great importance in providing evidence for the accurate targeting of tau oligomers. The global population of ageing humans is increasing each year; hence, the need to develop methods to slow down the onset and progression of various neurodegenerative diseases is also expanding. This study provides a positive step towards addressing that need.
https://onlinelibrary.wiley.com/doi/10.1111/acel.13615
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fcentral-role-for-p62&filter=22
Protecting the brain from dementia-inducing abnormal protein aggregates
- 947 views
- Added
Latest News
Ancient viral DNA in the hu…
By newseditor
Posted 26 May
AI to analyze clumping prot…
By newseditor
Posted 26 May
Reversible, non-hormonal ma…
By newseditor
Posted 26 May
Dissection of the schizophr…
By newseditor
Posted 26 May
Protease action on controll…
By newseditor
Posted 25 May
Other Top Stories
Check-point inhibitors exacerbate NASH induced liver cancer
Read more
AI used to understand asbestos-linked cancer
Read more
Protein rewires cancer cell metabolism to promote metastasis
Read more
The role of hypoxia-inducible factors in tumor growth and suppression
Read more
Dual treatment to kill small cell lung cancer (SCLC) cells
Read more
Protocols
SEMORE: SEgmentation and MO…
By newseditor
Posted 26 May
Spatially resolved lipidomi…
By newseditor
Posted 24 May
Efficient expansion and CRI…
By newseditor
Posted 21 May
Massively parallel in vivo…
By newseditor
Posted 20 May
Breast cancer-on-chip for p…
By newseditor
Posted 16 May
Publications
Integrating human endogenou…
By newseditor
Posted 26 May
The thalamic reticular nucl…
By newseditor
Posted 26 May
PMI-controlled mannose meta…
By newseditor
Posted 26 May
Protein-membrane interactio…
By newseditor
Posted 26 May
Toward an interventional sc…
By newseditor
Posted 26 May
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar