Pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of Huntington's disease

Xiaofeng Gu,Véronique M André,Michael S Levine,Xiao-Jiang Li,Shi-Hua Li,Carlos Cepeda,X William Yang

doi:10.1186/1750-1326-2-8

Abstract

A critical issue in understanding Huntington's disease (HD) pathogenesis is how the ubiquitously expressed mutant huntingtin (mhtt) with an expanded polyglutamine repeat can cause selective toxicity of striatal and cortical neurons. Two potential cellular models may contribute to such specificity: expression of mhtt in these vulnerable neurons alone may be sufficient to result in their dysfunction and/or degeneration (cell-autonomous model); or mhtt in other cell types can elicit pathological cell-cell interactions to cause the vulnerable neurons to become dysfunctional and be at risk for degeneration (cell-cell interaction model). To distinguish between these two models, we have selectively expressed a neuropathogenic fragment of mhtt-exon1 in striatal medium spiny neurons (MSNs) by crossing a conditional mouse model of HD with a striatal-specific Cre mouse line. In this striatal model of HD, we observed progressive and cell-autonomous nuclear accumulation of mhtt aggregates in MSNs. Surprisingly, unlike the mouse model expressing mhtt-exon1 in all the neurons in the brain, the striatal model lacks significant locomotor deficits and striatal neuropathology including gliosis and dark degenerating neurons. Electrophysiological findings from acutely dissociated MSNs revealed a cell-autonomous deficit in N-methyl-d-aspartate (NMDA) receptor sensitivity to Mg2+, a deficit also present in other mouse models of HD. In conclusion, this study provides the first in vivo genetic evidence that pathological cell-cell interactions are necessary for striatal pathogenesis in a conditional mouse model of HD, and suggests a ''two-hit'' hypothesis in which both cell-autonomous toxicity and pathological cell-cell interactions are critical to HD pathogenesis.

Highlights

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized clinically by movement abnormalities, psychiatric symptoms, and cognitive deficits [1]
GFiegnuerreat1ion of the striatal specific mouse model of HD Generation of the striatal specific mouse model of HD. (A) Schematics illustrate the strategy to use cell-type-specific Cre to selectively activate mhtt-exon1 expression in all neurons in the brain, only in cortical pyramidal neuron (CPN), and only in striatal medium spiny neurons (MSNs) and a subset of interneurons in the cortex. (B) Immunohistochemical staining using polyclonal EM48 antibody, which is specific to aggregated forms of mhtt [9], reveals a cell-autonomous accumulation of nuclear mhtt aggregates in the striatum of the striatal model at 6 months of age
To address the role of pathological cell-cell interactions in striatal pathogenesis in HD mousemodels in vivo, we developed a striatum-specific mouse model of HD which expresses a neuropathological fragment of mhtt selectively in striatal MSNs and in a subset of cortical interneurons but not in the CPNs or other neurons in the brain

Summary

Introduction

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized clinically by movement abnormalities (i.e. chorea), psychiatric symptoms, and cognitive deficits [1]. In all polyglutamine disorders including HD, the polyQ repeat length is inversely correlated with the age of onset of symptoms [4,5,6,7,8]. Contrary to the significant neurodegeneration in the striatum and cortex, neurons in the cerebellum and other sub-cortical brain regions are usually spared in the majority of HD patients. The latter brain regions may exhibit some neurodegeneration only in the most severely affected, juvenile-onset HD patients who have relatively longer polyQ repeats [11]. Since mutant huntingtin (mhtt) is ubiquitously expressed in the brain and peripheral tissues [11,12,13], the selective pattern of neuronal toxicity in HD cannot be explained by the expression pattern of mhtt [14,15,16,17]

Methods

Results

Discussion

Conclusion