Proteostasis- Understanding protein recycling, and how we can maintain the balance
Ageing is inevitable; it seems obvious that as you age, you reach your peak and then decline into old age; exactly why this happens remains a mystery. During ageing, the cells in your body multiply, either replacing defective cells or helping you grow and repair any injuries. You are essentially a clone of yourself, entirely renewed every seven years or so; every cell in your body is built to replicate itself, a copy of a copy, multiplied by countless trillions.
How a cell replicates itself depends on its function, either surviving by itself or as part of a greater organism. All cells contain the same genetic information, the type of cell it becomes depends on how the DNA code is translated, with specific regions of DNA responsible for the creation of specific proteins, chains of bespoke amino-acids that fold into the biological cogs, tailored for the task at hand. Which proteins are produced depends on epigenetics, a process controlling how the DNA in the cell is folded, and which parts of the code are accessible for protein synthesis.
However, nobody’s perfect, and sometimes errors occur! Subtle changes in the amino-acid sequence can cause drastic changes in how the protein is folded, and ultimately its functionality, resulting in a cog that no longer fits the machinery. Most proteins are constructed in such a way that, as the chain of amino acids folds, the hydrophobic (water-hating) components are hidden within the 3D structure of the protein, away from the watery cytoplasm of the cell’s innards. However, when proteins cannot fold correctly, these hydrophobic regions may remain exposed, and if there are sufficient defective proteins, the hydrophobic regions of all these proteins start to clump together to form large plaques, which may eventually become toxic to the cell. However, cells have evolved a number of biological pathways to deal with these rogue proteins, before they cause any long-term damage, known as protein quality control (PQC) systems, a part of the delicate balance of “proteostasis”.
Two crucial PQC pathways have been identified: the ubiquitin-proteasome system and autophagy, mechanisms that identify any non-native toxic proteins, which are then broken down into shorter peptide chains or their constituent amino acids, to be reused by the cell. However, as organisms age, these proteostatic capabilities decline, and without these checks and balances, rogue proteins accumulate. In humans, many age-related disorders are linked to the presence of these misfolded proteins, including type 2 diabetes, Alzheimer’s, and Parkinson’s diseases. Although the importance of these proteostasis pathways has been recognised, and the researchers awarded Nobel prizes in 2004 and 2016, a better understanding of how these processes work, might facilitate the development of treatments for these diseases and so improve the health and quality of life of patients.
Dr Rahul Samant and his team at the Babraham Institute investigate these PQC pathways. By using cutting-edge molecular tools and modelling techniques, they focus on the proteins involved in these systems, and from observing how these change in older or diseased cells, hope to determine how a cell’s ability to maintain proteostatic conditions diminishes.
“By performing studies in a range of model systems—from single-celled budding yeast to humans—we hope to unravel underlying rules governing proteostasis conserved throughout evolution, development, and ageing.”
Dr Rahul Samant
This research focuses on the development of potential drugs that affect the intracellular movement of these misfolded proteins. Proteins determined to be defective or surplus by the ubiquitin-proteasome system are marked for destruction with the attachment of a number of small ubiquitin-proteins. The transportation of these ubiquitin marked-proteins is in part controlled by molecule chaperones, HSP90, which manoeuvre them to a proteasome, a specialised organelle that recycles proteins.
By better understanding, these biological pathways, the signalling research team at the Babraham Institute hope to develop effective treatments for many of the ailments associated with getting old and permit an ageing population to get the most out of their golden years without the worry of degenerative disorders. Ageing is inevitable, but maybe, with a better understanding of the internal mechanisms within cells, we can let everyone grow old a little more comfortably!
Further reading:
Institute, B., 2020. Rahul Samant » Babraham Institute. [online] Babraham.ac.UK. Available at: <https://www.babraham.ac.uk/our-research/signalling/rahul-samant> [Accessed 12 December 2020].
Johnston, H.E. and Samant, R.S., 2020. Alternative systems for misfolded protein clearance: life beyond the proteasome. The FEBS Journal.
Samant, R.S., Livingston, C.M., Sontag, E.M. and Frydman, J., 2018. Distinct proteostasis circuits cooperate in nuclear and cytoplasmic protein quality control. Nature, 563(7731), pp.407-411.
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