My recent favourites are actually quite surprising given that most of my life, I've been incredibly obsessed with pro-survival pathways like PI3K/AKT ERK1/2 and JAK2/STAT3. fingers, once I understood how these worked I discovered that The substances and enzymes normally implicated in cell death and neurodegeneration have some rather fascinating and cool biological effects independence of their cell killing mechanisms. furthermore, they generally only kill cells when highly activated for a long period of time.
These enzymes are; PTEN, P53, protein phosphatase2A(PP2A) and GSK3. an example of. A proapoptotic small molecule i've come to admire is ceramide which is a powerful activator of many protein phosphatases but especially PP2A. scientists have long thought about blocking these proteins and substances to treat neurodegeneration but never seem to get there, probably because these things have vital and amazing biological functions which are needed for the body and brain to function properly.
What are these amazing properties?:
Most relevant to the brain, protein phosphatases like PTEN and PP2A as well as GSK3 are needed to carry out long-term depression LTD which is the weakening of synaptic strength by removing glutamate receptors from the surface. most importantly, this helps protect against seizures and protects against development of epilepsy. secondly, it prevents saturation of synapses, thus allowing less useful or even harmful memories to be removed and replaced with new relevant ones. interestingly, many forms of autism including severe intellectual disability could be linked to a lack of these phosphatase protein activity.
In terms of neurotransmitter effects, PP2A and downstream GSK3 activity are needed for the behavioural effects of dopamine. I once read an article that warned about the unintended negative affects of using pro-survival strategies like PTEN inhibitors for Parkinson's disease. this is because, whilst switching off. PTEN could theoretically protect dopaminergic neurons, it could also prevent The dopamine D2 receptor from carrying out its downstream functions like stimulating movements in response to dopamine.
In terms of biological effects outside the body, PTEN and many other protein phosphatases are needed to switch off excessive insulin signalling. yes, under conditions of obesity this does lead to insulin resistance and possibly diabetes. however, many people may not realise that insulin resistance is actually a protective mechanism that protects individual cells against nutrients overload and also spares glucose for the brain, thus preventing potentially deadly hypoglycaemia. actually, many researchers have been pushing for the development of drugs that block ceramide production, because apparently doing so can completely prevent insulin resistance even in the face of extremely high fat and sugar diets. yet again, this has never gone beyond lab testing in animals. that's probably because these drugs would have many unintended toxic effects and I imagine they would carry the risk of severe hypoglycaemia. they would also probably promote massive fat storage by enhancing insulin signalling. Note that ceramide works by activating protein phosphatases to switch off AKT which in tern switches off insulin signalling. many may not know this, but insulin resistance can actually promote fat loss because fat cells are less likely to take up glucose and are more likely to release fatty acids into the bloodstream. how long as you exercise, these fatty acids will be burnt off and harm should be minimised. This might be one of the reasons why weight loss is quite easy when starting a weight loss program, but slows down as you lose weight.
These next two points are closely related. Firstly, traditionally proapoptotic proteins like P 53 and above mentioned protein phosphatases can have pro-survival functions by helping cells to adapt to extreme environments. for example, they can enhance fatty acid oxidation as an alternative source of energy, induce antioxidant enzyme expression, slowdown nutrient uptake to prevent nutrient overload and slow down. or halt cell division under conditions of extreme starvation or stress when there is a risk that dividing could actually kill both cells.
Finally, it should be noted that all the proapoptotic proteins I have mentioned generally kill cells when strongly activated and they do so by pretty much the same downstream mechanisms. usually this is rupture of the mitochondrial membrane and activation of CASPASES. however, the beneficial biological effects of these proteins and their small molecule activators like ceramide are actually completely separate from their proapoptotic function.
What does this mean for medical research?
Well, at least in my opinion, it means that blocking things like protein phosphatases or GSK3 is not the answer. Instead, we should focus on blocking their downstream interactions with the mitochondria, which is actually the cause of cell damage and cell death. some scientist have been investigating this, and have demonstrated that it can be done with small molecules.
