Dr. Maiuri’s research for the next three years will be extending from her 2017 Human Molecular Genetics publication:
Huntingtin is a scaffolding protein in the ATM oxidative DNA damage response complex.
Maiuri T, Mocle AJ, Hung CL, Xia J, van Roon-Mom WM, Truant R. Hum Mol Genet. 2017 Jan 15;26(2):395-406. doi: 10.1093/hmg/ddw395. PMID:28017939
This was the first manuscript to define endogenous human huntingtin as a DNA repair protein and to discover that a pathway defective in HD is in common with many genetic ataxias. This work puts forth a new hypothesis for Huntington’s disease: That the age-onset trigger of this disease is elevated Reactive Oxygen Species (ROS) damage to neuronal DNA, which is supposed to be corrected by huntingtin protein, but is actually inhibited by the mutant huntingtin protein in HD. For these studies, Dr. Maiuri took the approach of avoiding models of disease with synthetic alleles by instead focusing on human cells derived from HD patients with typical clinical HD alleles of CAG 40-45. These new lines are now being shared with the HD research community, and importantly, these lines are not transformed to cancer cells by inhibition of P53.
P53 is critical to understanding Huntington’s disease, as this critical node for cancer is also critical for DNA damage repair and a known activator of huntingtin protein. P53 regulated proteins, in addition to huntingtin, have been discovered as significant modifiers of HD age of onset from HD genome-wide association studies (GWAS). This 2015 manuscript in CELL:
Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease.
Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Cell. 2015 Jul 30;162(3):516-26. doi: 10.1016/j.cell.2015.07.003.
And this study of the significant HD genes in other CAG expansion diseases:
DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases.
Bettencourt C, Hensman-Moss D, Flower M, Wiethoff S, Brice A, Goizet C, Stevanin G, Koutsis G, Karadima G, Panas M, Yescas-Gómez P, García-Velázquez LE, Alonso-Vilatela ME, Lima M, Raposo M, Traynor B, Sweeney M, Wood N, Giunti P; SPATAX Network, Durr A, Holmans P, Houlden H, Tabrizi SJ, Jones L. Ann Neurol. 2016 Jun;79(6):983-90. doi: 10.1002/ana.24656
Indicate that when we look at humans with these diseases in an unbiased manner, the pathways that influence these diseases by decades are related to ROS control, and DNA repair, which makes sense in terms of the age-onset aspect of these diseases: as the CAG alleles are expanded, the ability of these patients to repair the everyday damage to their DNA is decreased. This is why the Truant lab is now taking a comparative Cell Biology and Chemical Biology approach to study Spinocerebellar Ataxia and Huntington’s diseases. The other reason is that these pathways are amenable to drugs.
Consistent with humans with HD, The Truant lab also defined a role of huntingtin as a ROS sensor. A single amino acid, one of 3,144 can allow huntingtin to sense elevated ROS outside of the nucleus, to them travel inside the nucleus to DNA damage caused by ROS.
Huntingtin N17 domain is a reactive oxygen species sensor regulating huntingtin phosphorylation and localization. DiGiovanni LF, Mocle AJ, Xia J, Truant R. Hum Mol Genet. 2016 Sep 15;25(18):3937-3945. doi: 10.1093/hmg/ddw234.
The future remains in people, not mice. Mouse models of this disease do not get sick at typical alleles seen in the clinic. Mice only live 9 months in the wild, and a few years in the lab. The ROS stress seem in human brains is just not seen in mice.
In the past, the Truant Lab defined the hypo-phosphorylation of huntingtin N17 domain as a defect in HD, which appeared to be corrected by IKK beta kinase inhibitors.
Kinase inhibitors modulate huntingtin cell localization and toxicity.
Atwal RS, Desmond CR, Caron N, Maiuri T, Xia J, Sipione S, Truant R. Nat Chem Biol. 2011 May 29;7(7):453-60. doi: 10.1038/nchembio.582.
Now, we realize that IKK kinase inhibition and inhibition of NFKb signaling can increase ROS damage to DNA, which triggers CK2 kinase activity on huntingtin N17.
Dr. Maiuri’s goals will be to define exactly how huntingtin is involved in DNA damage repair, in humans. Already consistent with her work, Dr. Rachel Harding, at the University of Toronto, has been using pure, full huntingtin to discover that this protein can bind DNA. Our hope is that Dr. Maiuri’s studies will reinforce the first fundamentally new hypothesis in HD research towards a therapeutic in almost 25 years.
Ouch. Some of those reviewer comments hurt. This is a direct consequence of character-limiting applications, structured reviews and virtual reviewing. Add to this the need to stretch out expertise of reviewers in order to get enough in each reviewers pile to rank and you will inevitably rely on peripheral expertise.
Given CIHR has, at last, abandoned such practices for the next Project grant competition, the Foundation competition is left to shrivel on the vine as its scale now lacks the basic fundamentals to allow expert review.
I do not understand why this carbuncle is persisting.