HD Insights™

4 HD Insights, Vol. 13 H D I N S I G H T S Copyright © Huntington Study Group 2016. All rights reserved. Highly cited: Astrocytes, cont… To our surprise, we found that exposing wild-type mice to equivalent increases in K + reproduced the elevated excitability features of MSNs described in a variety of HD mouse models. We then delivered Kir4.1-GFP channels to striatal astrocytes in HD-model mice by using adeno-associated viruses, and found that one motor symptom (stride length and width) was attenuated by this approach. We also found that MSN membrane properties were partly recovered by astrocyte expression of Kir4.1-GFP in R6/2 mice, strongly supporting the notion that some HD-like phenotypes derive from neuronal dysfunction that itself derives, in part, from astrocyte disturbances. To date, research efforts have been focused almost exclusively on identifying neuronal cell-autonomous mechanisms to account for changes in MSN properties in HD models. Our findings provide evidence that key aspects of altered MSN excitability in HD are secondary to disturbance of astrocyte maintenance of extracellular K + . The precise cellular functions of HTT are not known, and it is not clear how mHTT impacts Kir4.1. Interestingly, transcriptome profiling of astrocyte responses to inflammatory mediators revealed HTT at the center of one of the top three most significantly altered gene networks. 5 This intriguing finding warrants further exploration. Overall, our findings show that aspects of altered neuronal excitability associated with HD may be secondary to changes in astrocyte function, thereby revealing striatal astrocytes as potential therapeutic targets for drug development. Interestingly, astrocytes display a distinctly different library of molecules compared to neurons. Further studies are warranted to determine whether astrocyte-specific molecular processes and pathways can be exploited to produce desirable effects, either directly or indirectly, on neural circuits in brain disease. This study was supported by the CHDI Foundation (BSK, MVS) and partly by the NIH (NS060677, MH104069 to BSK). By: Carolin A. M. Koriath, MD, Davina J. Hensman Moss, BA, MBBS, Sarah J. Tabrizi, MBChB, PhD C9orf72 expansions and HD phenocopies HD is the most common genetically determined neurodegenerative disease. 1 This autosomal dominant condition, caused by a CAG repeat expansion in the huntingtin gene, is typically defined by a triad of movement, cognitive, and psychiatric symptoms. However, while chorea is common and usually accompanied by cognitive decline, patients can also suffer from akinetic-rigid syndromes, dystonia, ataxia, as well as solely cognitive or psychiatric symptoms, 2 which can complicate clinical diagnosis. Approximately 1% of those with suspected HD do not carry the CAG expansion in the huntingtin gene. 3,4 These patients suffer from so-called HD phenocopy syndromes; differential diagnoses include HD-like syndromes (HDL) 1, 2, and 3, spino-cerebellar atrophy 17, and dentatorubral-pallidoluysian atrophy. 5 An intronic hexanucleotide repeat expansion in the C9orf72 gene 6 was first described in 2011 as the most frequent cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). 7-10 The expansion has since been identified in additional syndromes, such as cerebellar ataxia. 11 In our study, 12 514 patients, who had been referred for HD testing by an experienced specialist and tested negative for the HTT CAG expansion, were examined for the C9orf72 expansion to establish whether it should be included in the routine genetic assessment for this patient cohort. Ten patients (1.95%, 95% confidence interval) were found to carry the C9orf72 GGGGCC repeat expansion, as well as the associated risk allele (rs3849942 A), either homo- or heterozygously. The size of the expansion did not differ significantly from other C9orf72-mediated syndromes or between those with and without chorea/dystonia. At almost 2%, this is the most frequently identified cause of HD phenocopy syndromes in a United Kingdom cohort. While 70% of the C9orf72 positive cases had a family history of neurodegenerative disease, 30% did not, leaving sporadic cases a possibility. Furthermore, while the reported age of onset of C9orf72-caused disease is approximately 57 years of age, in this cohort it was 42.7 years, broadening not only the phenotype, but also the demographic in which this diagnosis should be considered. True HD and HD phenocopy syndromes can present with a spectrum of cognitive, psychiatric, and movement symptoms, and without an obvious family history. C9orf72-caused disease can also present with a very heterogenous range of symptoms from FTLD/ALS to parkinsonism. 13 We therefore propose that genetic testing for C9orf72 should be included in the clinical algorithm for the HD phenocopy work-up, following the test for the HTT expansion, and preceding the test for spino-cerebellar ataxia 17. Original Article: C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies (cited 28 times as of 2/8/2016) 1 Khakh BS, Sofroniew MV. Diversity of astrocyte functions and phenotypes in neural circuits. Nat Neurosci. 2015;18:942-952. 2 Ringel M, Tollman P, Hersch G, Schulze U. Does size matter in R&D productivity? If not, what does? Nat Rev Drug Discov. 2013;12:901-902. 3 Bradford J, Shin JY, Roberts M, et al. Expression of mutant huntingtin in mouse brain astrocytes causes age-dependent neurological symptoms. Proc Natl Acad Sci U S A. 2009;106:22480-22485. 4 Tong X, Ao Y, Faas GC, et al. Astrocyte Kir4.1 ion channel deficits contribute to neuronal dysfunction in Huntington's disease model mice. Nat Neurosci. 2014;17:694-703. 5 Hamby ME, Coppola G, Ao Y, et al. Inflammatory mediators alter the astrocyte transcriptome and calcium signaling elicited by multiple G-protein-coupled receptors. J Neurosci. 2012;32:14489-14510.

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