Proteostasis

• This is Deinococcus radiodurans, one of the most resistant bacteria known to date, which lives in arid environments such as desert sand.
• It can also overcome an irradiation dose 5,000 times greater than the lethal dose for humans.

• Its DNA isn’t resistant, it’s simply repaired immediately by proteins that are indestructible in the face of this extreme radiation.
• Hence the secret of the robustness of this extremophilic bacterium depends on the robustness of its “proteome” – the sum of all its proteins – and in particular its DNA repair proteins.

The keys to ageing

• Numerous models have been proposed to explain the molecular basis of ageing, such as the theory of cellular senescence, the reduction in DNA repair capacity, telomere shortening, mitochondrial dysfunction and oxidative stress or chronic inflammation.
• These different models all attempt to understand the consequences of ageing, not the causes.

Indeed, rather than focusing on our DNA and trying to protect it to slow down our ageing, what if we protected our proteome?

What is the proteome?

• Proteins – from the Greek protos meaning “first” – are only exceeded as a constituent of the human body by water, and account for around 20% of its mass.
• The term was coined by analogy with the genome: the proteome being to proteins what the genome is to genes, i.e.
• the set of genes/proteins of an individual – this protein set varying according to the activity of the genes.

A structural role: many proteins are central to the maintenance and cohesion of our tissues. For example, actin and tubulin are involved in cell architecture. Keratin is involved in the architecture of our epidermis, hair and nails. Collagen is a protein that plays an important role in the structure of bones, cartilage and skin.
A functional role: enzymatic (for example, proteases are involved in cleaning up dysfunctional proteins and in desquamation), hormonal (for example, insulin regulates glycaemia), transport (for example, aquaporins transport water in the different layers of the skin) or defence (for example, immunoglobulins are involved in the immune response). All vital functions are thus ensured by the activity of proteins.

Carbonylation, the leading cause of irreparable damage to our proteome

• It is under constant threat, because protein synthesis and degradation also depend on proteins.
• Over time and as a result of external aggression, the proteome is subjected to various alterations, the most formidable of which is carbonylation, irreversible damage linked to the oxidation of proteins.
• These carbonylated protein aggregates are found in most age-related diseases, as well as in the main signs of skin ageing.

Antioxidant chaperone molecules to act on the causes of ageing

To correctly perform their many jobs, proteins need to fold into a range of shapes and are helped out by specialised proteins called “chaperones”. These help out the proteins after their synthesis by ribosomes, or their correct folding after stress, such as heat.

• In short, chaperones (protein or chemical) are the doctors of malformed proteins.
• At the same time, their antioxidant effectiveness neutralises the causes of carbonylation.
• In Deinococcus radiodurans, because its proteome is protected against oxidative damage by chaperone molecules, it remains intact and can then able to repair damage to its genome.

Miroslav Radman is founder and scientific director of the Mediterranean Institute for Life Sciences (MedILS). The MedILS has received funding from the NAOS company for several research collaborations. He is a consultant and member of the NAOS Scientific Committee.

• TOKYO, Dec 19, 2023 - (JCN Newswire) - Eisai Co., Ltd. announced today that it has submitted a marketing authorization application in Japan for its in-house discovered fibroblast growth factor (FGF) receptor (FGFR1, FGFR2, FGFR3) selective tyrosine kinase inhibitor tasurgratinib succinate (generic name, development code: E7090, "tasurgratinib") for biliary tract cancer with FGFR2 gene fusion.
• In Japan, tasurgratinib has received orphan drug designation for a prospective indication for unresectable biliary tract cancer with FGFR2 gene fusion by the Ministry of Health, Labour and Welfare, (MHLW).
• This application is based on the results of a multicenter, open-label, single-arm clinical phase II trial (Study 201) in Japan and China conducted by Eisai.
• Study 201 enrolled patients with unresectable biliary tract cancer with FGFR2 gene fusion previously treated with gemcitabine-based combination chemotherapy.

• SAN RAFAEL, Calif., Dec. 20, 2023 /PRNewswire/ -- BioMarin Pharmaceutical Inc. (NASDAQ: BMRN), a global biotechnology company dedicated to transforming lives through genetic discovery, today announced several initiatives to enhance corporate governance and long-term shareholder value creation.
• "Today's announcements will strengthen our ability to drive better outcomes for patients with genetic diseases and deliver value to all stakeholders.
• BioMarin plays a pivotal role in the treatment of genetic diseases thanks to its globally leading rare-disease portfolio.
• We believe the changes announced today put BioMarin in the best position to realize its full potential, and we support Alexander Hardy as the right leader for this chapter of BioMarin's value creation story.

• In this free webinar, explore insights into targeted protein degradation (TPD) and learn new avenues for enhanced treatment efficacy through selective protein removal.
• TORONTO, Dec. 18, 2023 /PRNewswire-PRWeb/ -- Discover a webinar delving into targeted protein degradation (TPD), an approach using cellular machinery to selectively remove proteins, promising more effective treatments with minimized side effects.
• Join this webinar to explore insights into TPD and learn new avenues for enhanced treatment efficacy through selective protein removal.
• Join Yongheng Huang, Doctor in Biochemistry, Protein Senior Scientist, GenScript , for the live webinar on Thursday, January 11, 2024, at 9am EST (3pm CET/EU-Central).