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.
Highlights
Huntington’s disease (HD) is an autosomal dominant genetic dis- degeneration [1,2]
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
Major clinical HD features include progressive 120 order that results from mutations leading to abnormal expansion development of behavioral disturbances, cognitive deterioration of a polyglutamine tract within the protein huntingtin and motor abnormalities [3]
Summary
Huntington’s disease (HD) is an autosomal dominant genetic dis- degeneration [1,2]. Major clinical HD features include progressive 120 order that results from mutations leading to abnormal expansion development of behavioral disturbances, cognitive deterioration of a polyglutamine ( polyQ) tract within the protein huntingtin and motor abnormalities [3]. Despite these changes, quantitation of 755 quantitative data showing a reduction in mean callosal axon YFP-positive neuronal cell bodies revealed similar numbers becaliber of YFP(J16)-R6/2(160Q), compared with YFP(J16) mice (10.47 ± 6.9 versus 20.3 ± 9.2 μm; n = 3 mice and 1500 axons per tween YFP(J16) and YFP(J16)-R6/2(160Q) mice (P30: 32 ± 5 versus 31 ± 12; P60: 33 ± 7 versus 30 ± 8; P90: 32 ± 9 versus 32 ± 11; n = 3 genotype) (Fig. 4E). Using the well-characterized EM48 antibody [40], we evaluated temporal and spatial correlations between degenerating callosal axons and mhtt aggregates in YFP[16]-R6/2
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