Format

Send to

Choose Destination
Hum Mol Genet. 2015 Sep 15;24(18):5285-98. doi: 10.1093/hmg/ddv248. Epub 2015 Jun 29.

Analysis of YFP(J16)-R6/2 reporter mice and postmortem brains reveals early pathology and increased vulnerability of callosal axons in Huntington's disease.

Author information

1
Department of Anatomy and Cell Biology, University of Illinois at Chicago, 808 S. Wood St., Rm 578 M/C 512, Chicago, IL 60612, USA.
2
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA and.
3
Department of Bioengineering, University of Illinois at Chicago, Chicago, IL 60612, USA.
4
Department of Anatomy and Cell Biology, University of Illinois at Chicago, 808 S. Wood St., Rm 578 M/C 512, Chicago, IL 60612, USA, gmorfini@uic.edu.

Abstract

Cumulative evidence indicates that the onset and severity of Huntington's disease (HD) symptoms correlate with connectivity deficits involving specific neuronal populations within cortical and basal ganglia circuits. Brain imaging studies and pathological reports further associated these deficits with alterations in cerebral white matter structure and axonal pathology. However, whether axonopathy represents an early pathogenic event or an epiphenomenon in HD remains unknown, nor is clear the identity of specific neuronal populations affected. To directly evaluate early axonal abnormalities in the context of HD in vivo, we bred transgenic YFP(J16) with R6/2 mice, a widely used HD model. Diffusion tensor imaging and fluorescence microscopy studies revealed a marked degeneration of callosal axons long before the onset of motor symptoms. Accordingly, a significant fraction of YFP-positive cortical neurons in YFP(J16) mice cortex were identified as callosal projection neurons. Callosal axon pathology progressively worsened with age and was influenced by polyglutamine tract length in mutant huntingtin (mhtt). Degenerating axons were dissociated from microscopically visible mhtt aggregates and did not result from loss of cortical neurons. Interestingly, other axonal populations were mildly or not affected, suggesting differential vulnerability to mhtt toxicity. Validating these results, increased vulnerability of callosal axons was documented in the brains of HD patients. Observations here provide a structural basis for the alterations in cerebral white matter structure widely reported in HD patients. Collectively, our data demonstrate a dying-back pattern of degeneration for cortical projection neurons affected in HD, suggesting that axons represent an early and potentially critical target for mhtt toxicity.

PMID:
26123489
PMCID:
PMC4550824
DOI:
10.1093/hmg/ddv248
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center