Two Causes of Autism Found to be Cellular Opposites
Two genetic diseases, Fragile X syndrome and tuberous sclerosis, both cause autism and intellectual disabilities by similar pathophysiological means: abnormal amounts of proteins produced by brain cells, especially at the cleft of synaptic junctions. In a recent study, Howard Hughes scientist Mark Bear attempts to investigate if such a similarity in pathophysiologal pathways might bear out a similar treatment for both diseases. What is striking about the conclusions of the study is that while Fragile X syndrome and tuberous sclerosis do in fact share symptomatic traits, chiefly autism, at the molecular level the symptoms are produced by extreme ends of a spectrum: Fragile X syndrome is an excessive synthesis of proteins in brain cells, whereas tuberous sclerosis is a depressed synthesis of similar proteins. The findings suggest that for normal function to occur, brain cells must produce synaptic proteins in a carefully defined range.
What I found to be very interesting concerning this article is the methodology of the scientists to test their hypotheses and draw their conclusions. A decade ago, Bear’s laboratory at MIT discovered that Fragile X syndrome was caused primarily by a mutation in Fmr1 gene, the gene responsible for regulating the activity of mGluR5 receptor. Without such regulation from Fmr1, mGluR5 would inappropriately synthesis excess synaptic proteins. Tuberous sclerosis, on the other hand, is caused by a mutation in the Tsc1 or Tsc2, which leads to abnormally excessive activity in a protein known as mTOR. Bear reasoned that since both genetic diseases exhibited similar pathophysiology, then mTOR must’ve worked through the same pathway as mGluR5, and that both produced excess amounts of synaptic proteins. However, Bear’s findings were in fact the opposite, and increased mTOR activity in mutated genes caused a depression in synaptic protein synthesis. Furthermore, Bear took his investigations a step further and introduced to Tuberous sclerosis mouse models treatments which promoted mGluR5 activity, the same overactivity which leads to Fragile X syndrome. By combining both pathophysiology of the two diseases together in the same model mouse, Bear was able to produce a mouse model which had normal synaptic protein levels. In conclusion, similar genetic diseases with seemingly similar pathophysiology might not be treatable in the same exact manner since they could be in fact extremes of a narrowly defined normal range.