Angelman Today September / October edition 2013 | Page 30

continued.. …………… of data or talk at a conference. It took time and data for the Reticular Theory and eventually the Neuronal Doctrine. So it goes with Angelman syndrome research; it is evolving. In the next issue we can discuss the accumulation of recent papers and published research and what it means for the Angelman Doctrine. On a side note, Cajal and Golgi remained friends throughout their careers despite being on opposite sides of the Neuronal Doctrine. Article of interest: Title: Topoisomerases facilitate transcription of long genes linked to autism Authors: Ian F. King, Chandri N. Yandava, Angela M. Mabb, Jack S. Hsiao, Hsien-Sung Huang, Brandon L. Pearson, J. Mauro Calabrese, Joshua Starmer, Joel S. Parker, Terry Magnuson, Stormy J. Chamberlain, Benjamin D. Philpot & Mark J. Zylka Abstract: Topoisomerases are expressed throughout the developing and adult brain and are mutated in some individuals with autism spectrum disorder (ASD). However, how topoisomerases are mechanistically connected to ASD is unknown. Here we find that topotecan, a topoisomerase 1 (TOP1) inhibitor, dose-dependently reduces the expression of extremely long genes in mouse and human neurons, including nearly all genes that are longer than 200 kilobases. Expression of long genes is also reduced after knockdown of Top1 or Top2b in neurons, highlighting that both enzymes are required for full expression of long genes. By mapping RNA polymerase II density genome-wide in neurons, we found that this length-dependent effect on gene expression was due to impaired transcription elongation. Interestingly, many high-confidence ASD candidate genes are exceptionally long and were reduced in expression after TOP1 inhibition. Our findings suggest that chemicals and genetic mutations that impair topoisomerases could commonly contribute to ASD and other neurodevelopmental disorders. Topoisomerase inhibitors are being considered as a potential therapeutic for AS. This article exemplifies the non-specific actions of topoisomerase inhibitors on many genes and suggests a link between chemicals that may act on topoisomerases and Autism. www.Medipal.com WWW.ANGELMANTODAY.COM September / October 2013