Meeting Professor Luisa Guerrini and finding her previous research has shown that thalidomide, isotretinoin and sertraline have similar effects on p63 is where the idea for this research forum first came from. The discovery of the effects of thalidomide on these regulatory protein holds out promise that we might finally over sixty years later find out how thalidomide causes birth defects – and sexual dysfunction.
Thalidomide overlaps a lot with SSRIs and isotretinoin, but they are not identical and the hope is that the SSRIs and isotretinoin may offer some missing pieces of the thalidomide jigsaw and this may shed light on their common problems.
p63 and p73 are transcription factors that belong to one of the most important gene families in vertebrate biology, the p53-family.
P63 is critically important for basic cellular functions during development of the skin, limb, palate and hair.
Many hereditary diseases are associated with mutations of the p63 gene. Mutations in the p63 gene have been associated to the following syndromes: Ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome (EEC); Split-hand/foot malformation syndrome (SHFM); Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC); Acro-dermato-ungual-lacrimal-tooth syndrome (ADULT); Limb-mammary syndrome (LMS); and Rapp-Hodgkin syndrome (RHS).
While there is no evidence of p63 functions in neuronal development, ever more research suggests a role for p53 in the adult neural precursor cell (NPC) maintenance. These are the cells that maintain adult neurogenesis.
They can be reduced in number by p63, by haploinsufficiency, due to enhanced apoptosis of NPCs, suggesting that p63 regulates the numbers of adult NPCs and that it does so by inhibiting p53-dependent cell death.
Reducing p63 protein levels could therefore be detrimental for NPC maintenance and neuronal functions.
p73 is involved in neuronal development and in the regulation of fertility.
p73 has been shown to be critical for the self-renewal of NPCs in the embryonic and adult brain, regulating the number of NPCs in the adult brain.
Perturbations in the expression or activity of any of these family members, by SSRI for example, will ultimately alter the size of the NPC pool, with significant repercussions for cognitive functions.
Neurogenesis is a complex process through which nerve cells are generated and integrated into existing neuronal circuits. Under normal conditions, adult neurogenesis takes place in two different regions of the brain and neural stem cells (NSC) play a key role in neurogenesis. They have the ability to differentiate into different brain cell types (neurons, astrocytes, and oligodendrocytes).
There is little research on this so far as it is hard to get the antibodies to p73 needed to carry out research.
p73 though appears to be co-expressed with a protein called Reelin and researching the functions of Reelin might offer leads.
Changes in the levels of p63, following SSRIs, and most probably also p73 due to the similarity between p63 and p73 proteins, could therefore lead to neural precursor cell and neural stem cells depletion or reduction.
Could this be linked to PSSD?