Tag Archives: Silencing Mediator of Retinoic acid and Thyroid hormone receptor

Progress has been slow but not for want of trying

Progress in the sense of therapy for Alzheimer’s disease and Glioblastoma multiforme is essentially nonexistent, and we could use better therapy for Parkinsonism. This doesn’t mean that researchers have given up. Far from it. Three papers all in last week’s issue of PNAS came up with new understanding and possibly new therapeutic approaches for all three.

You’ll need some serious molecular biological and cell physiological chops to get through the following.

l. Glioblastoma multiforme — they aren’t living much longer than they were when I started pracice 45 years ago (about 2 years — although of course there are exceptions).

The human ZBTB family of genes consists of 49 members coding for transcription factors. BCL6 is also known as ZBTB27 and is a master regulator of lymph node germinal responses. To execute its transcriptional activity, BCL6 requires homodimerization and formation of a complex with a variety of cofactors including BCL6 corerpressor (BCoR), nuclear receptor corepressor 1 (NCoR) and Silencing Mediator of Retinoic acid and Thyroid hormone receptor (SMRT). BCL6 inhibitors block the interaction between BCL6 and its friends, selectively killing BCL6 addicted cancer cells.

The present paper [ Proc. Natl. Acad. Sci. vol. 114 pp. 3981 – 3986 ’17 ] shows that BCL6 is required for glioblastoma cell viability. One transcriptional target of BCL6 is AXL, a tyrosine kinase. Depletion of AXL also decreases proliferation of glioblastoma cells in vitro and in vivo (in a mouse model of course).

So here are two new lines of attack on a very bad disease.

2. Alzheimer’s disease — the best we can do is slow it down, certainly not improve mental function and not keep mental function from getting worse. ErbB2 is a member of the Epidermal Growth Factor Receptor (EGFR) family. It is tightly associated with neuritic plaques in Alzheimer’s. Ras GTPase activation mediates EGF induced stimulation of gamma secretase to increase the nuclear function of the amyloid precursor protein (APP) intracellular domain (AICD). ErbB2 suppresses the autophagic destruction of AICD, physically dissociating Beclin1 vrom the VPS34/VPS15 complex independently of its kinase activity.

So the following paper [ Proc. Natl. Acad. Sci. vol. 114 pp. E3129 – E3138 ’17 ] Used a compound downregulating ErbB2 function (CL-387,785) in mouse models of Alzheimer’s (which have notoriously NOT led to useful therapy). Levels of AICD declined along with beta amyloid, and the animals appeared smarter (but how smart can a mouse be?).

3.Parkinson’s disease — here we really thought we had a cure back in 1972 when L-DOPA was first released for use in the USA. Some patients looked so good that it was impossible to tell if they had the disease. Unfortunately, the basic problem (death of dopaminergic neurons) continued despite L-DOPA pills supplying what they no longer could.

Nurr1 is a protein which causes the development of dopamine neurons in the embryo. Expression of Nurr1 continues throughout life. Nurr1 appears to be a constitutively active nuclear hormone receptor. Why? Because the place where ligands (such as thyroid hormone, steroid hormones) bind to the protein is closed. A few mutations in the Nurr1 gene have been associated with familial parkinsonism.

Nurr1 functions by forming a heterodimer with the Retinoid X Receptor alpha (RXRalpha), another nuclear hormone receptor, but one which does have an open binding pocket. A compound called BRF110 was shown by the following paper [ Proc. Natl. Acad. Sci. vol. 114 pp. 3795 – 3797, 3999 – 4004 ’17 ] to bind to the ligand pocked of RXRalpha increasing its activity. The net effect is to enhance expression of dopamine neuron specific genes.

More to the point MPP+ is a toxin pretty selective for dopamine neurons (it kills them). BRF110 helps survival against MPP+ (but only if given before toxin administration). This wouldn’t be so bad because something is causing dopamine neurons to die (perhaps its a toxin), so BRF110 may fight the decline in dopamine neuron numbers, rather than treating the symptoms of dopamine deficiency.

So there you have it 3 possible new approaches to therapy for 3 bad disease all in one weeks issue of PNAS. Not easy reading, perhaps, but this is where therapy is going to come from (hopefully soon).

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