A rat model of Charcot–Marie–Tooth disease 1A recapitulates disease variability and supplies biomarkers of axonal loss in patients

摘要: Charcot-Marie-Tooth disease is the most common inherited neuropathy and a duplication of peripheral myelin protein 22 gene causes frequent subform 1A. Patients develop slowly progressive dysmyelinating demyelinating distally pronounced muscle atrophy. The amount axonal loss determines severity. Although patients share an identical monogenetic defect, progression strikingly variable impending course can not be predicted in individual patients. Despite promising experimental data, recent therapy trials have failed. Established clinical outcome measures are thought to too insensitive detect amelioration within trials. Surrogate biomarkers severity 1A thus urgently needed. Peripheral transgenic rats harbouring additional copies ('Charcot-Marie-Tooth rats'), which were kept on outbred background mimic hallmarks phenocopy with Hence, we used rat dissect prospective surrogate markers derived from sciatic nerve skin tissue messenger RNA extracts. Gene set enrichment analysis transcriptomes revealed that dysregulation lipid metabolism associated genes such as peroxisome proliferator-activated receptor gamma constitutes modifier present future Importantly, directly validated 46 Our data suggest combination age cutaneous levels glutathione S-transferase theta 2 cathepsin A composes strong indicator 1A, quantified by Neuropathy Score. This translational approach, utilizing animal model, demonstrates transcriptional biopsy suitable identify