Cereblon & Lon protease

From a  discussion with OS on MedCram (which had gone way OT from sex differences relating to covid-19 pathology - link to discussion thread):

re: AMPK bat genetics - not much yet, but there's this one

Positive Selection of Cereblon Modified Function Including Its E3 Ubiquitin Ligase Activity and Binding Efficiency With AMPK - https://pubmed.ncbi.nlm.nih.gov/30836149/

Note the same modification is present in both bats and rodents. Hamsters do seem to have some protection from oxidative stress, but they are not particularly long-lived as are bats. They are what's termed 'r selected' - with a life history characterized by high reproductive rate and short life-span.

Here's an article that points out that oxidative stress defenses may be tissue specific and that hamsters may not have as much protection in the brain:

Oxidative Damage Does Not Occur in Striped Hamsters Raising Natural and Experimentally Increased Litter Size - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624642/

I suspect bats really need their brains protected to preserve their echolocation ability, though the cereblon modification is in both bats and rodents, so hmmm... - this is a very interesting topic.

I have started to read up on cereblon.

Mitochondrial Cereblon Functions as a Lon-type Protease [2016] - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945938/

“Lon protease plays a major role in the protein quality control system in mammalian cell mitochondria. It is present in the mitochondrial matrix, and degrades oxidized and misfolded proteins, thereby protecting the cell from various extracellular stresses, including oxidative stress. The intellectual disability-associated and thalidomide-binding protein cereblon (CRBN) contains a large, highly conserved Lon domain. However, whether CRBN has Lon protease-like function remains unknown. Here, we determined if CRBN has a protective function against oxidative stress, similar to Lon protease. We report that CRBN partially distributes in mitochondria, suggesting it has a mitochondrial function. To specify the mitochondrial role of CRBN, we mitochondrially expressed CRBN in human neuroblastoma SH-SY5Y cells. The resulting stable SH-SY5Y cell line showed no apparent effect on the mitochondrial functions of fusion, fission, and membrane potential. However, mitochondrially expressed CRBN exhibited protease activity, and was induced by oxidative stress. In addition, stably expressed cells exhibited suppressed neuronal cell death induced by hydrogen peroxide. These results suggest that CRBN functions specifically as a Lon-type protease in mitochondria.

Lon protease is a highly conserved ATP-dependent serine peptidase in both prokaryotes and eukaryotes, and is required for maintenance of mitochondrial homeostasis24. It plays a pivotal role in mitochondrial protein quality control by degrading oxidized and misfolded proteins generated within the mitochondrial matrix25,26,27. Lon protease is also a stress protein that is induced by multiple stressors such as oxidative stress, heat shock, and nutrient starvation28. During these stresses, the Lon gene is up-regulated and suppresses cell death28. Previous studies have shown that Lon protease overexpression provides apoptotic resistance to oxidative stress in human and fungal cells29,30. By contrast, reduced levels and activities of Lon protease are associated with the aging process. In such conditions, oxidized proteins accumulate in an age-related manner and cause mitochondrial dysfunction, which ultimately leads to cell death26,31. Accumulating evidence shows that the Lon protease acts as a key antioxidant in mitochondria by limiting oxidative damage to tolerable levels.”

Seems as though mouse models of neurodegenerative diseases should be modified to express human cereblon.

I suppose there a great many other differences between humans and mice, however. As OS alludes to further in the discussion, a defect in the T3 thyroid hormone transporter (mct8) in humans is sufficient in humans to cause  Allan-Herndon-Dudley syndrome, but the mouse model requires the additional knockout of oatp.