Developmental Whole Brain White Matter Alterations in Transgenic Huntington’s Disease Monkey

Abstract

Transgenic Huntington’s disease monkey (HD monkey) model provides great opportunity for studying disease progression that could lead to new insight for developing biomarker, early intervention and novel therapeutics. Whole brain white matter integrity of HD-monkeys was examined longitudinally from 6 to 48 months using diffusion tensor imaging (DTI) and tract-based spatial statistics (TBSS). Progressive developmental white matter alterations in HD monkeys were widespread and were observed not only in fiber bundles connecting cortical areas to the striatum (e.g. striatal bundle and external capsule), but also in long association fiber pathways, commissural fibers, and subcortical fiber bundle. In all fiber tracts, the data indicate an arrest in white matter development around 23 months followed by slight decline until adulthood in HD monkeys. The microstructural changes parallel the progressive motor, memory and cognitive decline previously reported as HD monkeys aged. The findings revealed the widespread progressive temporal-spatial microstructural changes in HD monkey brains from infancy to adulthood, suggesting differentiated degenerations across different brain areas during brain development.

Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

“…54 rHD6, rHD7 and rHD8 lines carry exons 1-10 of the hHTT gene coding N-terminal 508 amino acids with 67-72 CAG repeats under control of the human HTT promoter. 24,53,55…”

“…One of the obstacles to that research is the fact that rhesus macaques express only 10‐11 CAG repeats, while transition point for CAG repeats in humans is about 35 . Currently, data from 8 HD monkey lines have been reported, five of them being tested in a longitudinal study . Monkey lines rHD1, rHD2, rHD3, rHD4 and rHD5 expressing 29 (single gene copy), 83 (two gene copies), 84 (two gene copies), 27 (two gene copies) and 88 (two gene copies) have been created .…”

“…Monkey lines rHD1, rHD2, rHD3, rHD4 and rHD5 expressing 29 (single gene copy), 83 (two gene copies), 84 (two gene copies), 27 (two gene copies) and 88 (two gene copies) have been created . rHD6, rHD7 and rHD8 lines carry exons 1‐10 of the hHTT gene coding N‐terminal 508 amino acids with 67‐72 CAG repeats under control of the human HTT promoter …”

Local transgene expression and whole‐body transgenesis to model brain diseases in nonhuman primate

“…Moreover, HD monkey exhibited increased proinflammatory cytokines and higher induction of immune pathway genes compared to controls . Another seven transgenic monkeys were produced for longitudinal studies to study the transcriptomic pattern (n = 4) or the whole brain white matter integrity (n = 3) . Interestingly, germline transmission was confirmed by the detection of the transgene directly not only in the male germ cells, but also in embryonic stem cells derived from blastocyst obtained after microinjection of spermatozoa from transgenic male.…”

White matter changes in Huntington’s disease and the demyelination hypothesis: a critical review

“…WM changes have been reported both in animal models and in HD human carriers by histopathological postmortem studies (de la Monte et al, 1988;Halliday et al, 1998;Huang et al, 2015;Jin et al, 2015), and MRI studies (Bartzokis et al, 2007;Jin et al, 2015;Meng, Jiang, Bachevalier, Zhang, & Chan, 2017;Rosas et al, 2006Rosas et al, , 2018Tabrizi et al, 2009Tabrizi et al, , 2011. These have shown widespread WM volume loss (Aylward et al, 2011;Beglinger et al, 2007;Ciarmiello et al, 2006;Paulsen et al, 2008;Rosas et al, 2006;Tabrizi et al, 2009Tabrizi et al, , 2012Tabrizi et al, , 2011 and WM alterations at the microstructural and molecular level (Bartzokis et al, 2007;Dumas et al, 2012;Huang et al, 2015Huang et al, , 2015Jin et al, 2015;Mascalchi et al, 2004;Matsui et al, 2014;Reading et al, 2005;Rosas et al, 2006;Stoffers et al, 2010;Wang & Yang, 2019).…”