Cortical interneuron loss and symptom heterogeneity in Huntington disease

Kim, Eric; Thu, Doris; Tippett, Lynette J.; Oorschot, Dorothy E.; Hogg, Virginia M.; Roxburgh, Richard; Synek, Beth J.; Waldvogel, Henry J.; Faull, Richard L.M.

doi:10.1002/ana.24162

Cited by 65 publications

(53 citation statements)

References 44 publications

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“…Staining by IHC is similarly eliminated in the cerebellum (Airaksinen et al, ). Labeling of calbindin is consistent with previous reports (Kim et al, ). Calretinin (Swant, cat no. CG1, RRID:AB_10000342).…”

Section: Methodssupporting

confidence: 93%

Distribution of the creatine transporter throughout the human brain reveals a spectrum of creatine transporter immunoreactivity

Lowe

Faull

Christie

et al. 2014

J of Comparative Neurology

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Creatine is a molecule that supports energy metabolism in cells. It is carried across the plasma membrane by the creatine transporter. There has been recent interest in creatine for its neuroprotective effects in neurodegenerative diseases and its potential as a therapeutic agent. This study represents the first systematic investigation of the distribution of the creatine transporter in the human brain. We have used immunohistochemical techniques to map out its location and the intensity of staining. The transporter was found to be strongly expressed, especially in the large projection neurons of the brain and spinal cord. These include the pyramidal neurons in the cerebral cortex, Purkinje cells in the cerebellar cortex, and motor neurons of the somatic motor and visceromotor cranial nerve nuclei and the ventral horn of the spinal cord. Many other neurons in the brain also had some degree of creatine transporter immunoreactivity. By contrast, the medium spiny neurons of the striatum and the catecholaminergic neurons of the substantia nigra and locus coeruleus, which are implicated in neurodegenerative diseases, showed a very low to almost absent level of immunoreactivity for the transporter. We propose that the distribution may reflect the energy consumption by different cell types and that the extent of creatine transporter expression is proportional to the cell's energy requirements. Furthermore, the distribution indicates that supplemented creatine would be widely taken up by brain cells, although possibly less by those cells that degenerate in Huntington's and Parkinson's diseases.

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Section: Methodssupporting

confidence: 93%

Distribution of the creatine transporter throughout the human brain reveals a spectrum of creatine transporter immunoreactivity

Lowe

Faull

Christie

et al. 2014

J of Comparative Neurology

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“…Different studies have shown the involvement of multiple striatal cell types (MSNs, GINs, oligodendrocytes, and astrocytes) in addition to other cardinal brain regions and cell types in HD (34)(35)(36)(37). All of these cellular subtypes are elaborated in a regionaland temporal-specific manner during neural development.…”

Section: Discussionmentioning

confidence: 99%

Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington’s disease

Molero

Arteaga-Bracho

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

115

100

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Recent studies have identified impairments in neural induction and in striatal and cortical neurogenesis in Huntington’s disease (HD) knock-in mouse models and associated embryonic stem cell lines. However, the potential role of these developmental alterations for HD pathogenesis and progression is currently unknown. To address this issue, we used BACHD:CAG-CreERT2 mice, which carry mutant huntingtin (mHtt) modified to harbor a floxed exon 1 containing the pathogenic polyglutamine expansion (Q97). Upon tamoxifen administration at postnatal day 21, the floxed mHtt-exon1 was removed and mHtt expression was terminated (Q97CRE). These conditional mice displayed similar profiles of impairments to those mice expressing mHtt throughout life: (i) striatal neurodegeneration, (ii) early vulnerability to NMDA-mediated excitotoxicity, (iii) impairments in motor coordination, (iv) temporally distinct abnormalities in striatal electrophysiological activity, and (v) altered corticostriatal functional connectivity and plasticity. These findings strongly suggest that developmental aberrations may play important roles in HD pathogenesis and progression.

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“…Indeed, the PREDICT-HD and the Huntington Study Group investigations have shown that white matter abnormalities are one of the best predictors of diagnostic proximity to HD (Paulsen et al, 2010), and also correlates with cognitive impairment in pre-manifest cases of HD (Beglinger et al, 2005). On the other hand, selective changes in the complement of interneurons in primary motor cortex and cingulate cortex are strongly linked to symptom heterogeneity in HD, particularly with respect to motoric and mood disorders (Kim et al, 2014). Additional studies have also shown important cognitive correlates with volumetric changes in the nucleus accumbens and the thalamus during the prodromal phase of disease (Aylward et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

Arteaga-Bracho

Gulinello

Winchester

et al. 2016

Neurobiology of Disease

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The mutation in huntingtin (mHtt) leads to a spectrum of impairments in the developing forebrain of Huntington’s disease (HD) mouse models. Whether these developmental alterations are due to loss- or gain-of-function mechanisms and contribute to HD pathogenesis is unknown. We examined the role of selective loss of huntingtin (Htt) function during development on postnatal vulnerability to cell death. We employed mice expressing very low levels of Htt throughout embryonic life to postnatal day 21 (Hdhd•hyp). We demonstrated that Hdhd•hyp mice exhibit: (1) late-life striatal and cortical neuronal degeneration; (2) neurological and skeletal muscle alterations; and (3) white matter tract impairments and axonal degeneration. Hdhd•hyp embryos also exhibited subpallial heterotopias, aberrant striatal maturation and deregulation of gliogenesis. These results indicate that developmental deficits associated with Htt functions render cells present at discrete neural foci increasingly susceptible to cell death, thus implying the potential existence of a loss-of-function developmental component to HD pathogenesis.

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Cortical interneuron loss and symptom heterogeneity in Huntington disease

Abstract: These findings suggest that region-specific degeneration of cortical interneurons is a key component in understanding the neural basis of symptom heterogeneity in HD.

Cited by 65 publications

References 44 publications

Distribution of the creatine transporter throughout the human brain reveals a spectrum of creatine transporter immunoreactivity

Distribution of the creatine transporter throughout the human brain reveals a spectrum of creatine transporter immunoreactivity

Selective expression of mutant huntingtin during development recapitulates characteristic features of Huntington’s disease

Postnatal and adult consequences of loss of huntingtin during development: Implications for Huntington's disease

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