title: Age-related axonal swellings precede other neuropathological hallmarks in a knock-in mouse model of Huntington's disease.
abstract: Axon degeneration precedes cell body death in many age-related neurodegenerative disorders, often determining symptom onset and progression. A sensitive method for revealing axon pathology could indicate whether this is the case also in Huntington's disease (HD), a fatal, devastating neurodegenerative disorder causing progressive deterioration of both physical and mental abilities, and which brain region is affected first. We studied the spatio-temporal relationship between axon pathology, neuronal loss, and mutant Huntingtin aggregate formation in HD mouse models by crossing R6/2 transgenic and HdhQ140 knock-in mice with YFP-H mice expressing the yellow fluorescent protein in a subset of neurons. We found large axonal swellings developing age-dependently first in stria terminalis and then in corticostriatal axons of HdhQ140 mice, whereas alterations of other neuronal compartments could not be detected. Although mutant Huntingtin accumulated with age in several brain areas, inclusions in the soma did not correlate with swelling of the corresponding axons. Axon abnormalities were not a prominent feature of the rapid progressive pathology of R6/2 mice. Our findings in mice genetically similar to HD patients suggest that axon pathology is an early event in HD and indicate the importance of further studies of stria terminalis axons in man.
authors.affiliation: School of Life Sciences, The University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Marangoni
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Adalbert
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge, UK.
authors.forename: Lucie
authors.initials: L
authors.lastname: Janeckova
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Patrick
authors.affiliation: School of Life Sciences, The University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK.
authors.forename: Jaskaren
authors.initials: J
authors.lastname: Kohli
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Coleman
authors.affiliation: School of Life Sciences, The University of Nottingham Medical School, Queen's Medical Centre, Nottingham, UK. Electronic address: Laura.Conforti@nottingham.ac.uk.
authors.forename: Laura
authors.initials: L
authors.lastname: Conforti
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D001369:Axons / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D006816:Huntington Disease / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration; D012686:Septal Nuclei / Q000473:pathology
keywords: Axon pathology; Axonal swelling; HdhQ140; Huntington's disease; R6/2; Stria terminalis; Yellow fluorescent protein; mHTT aggregates