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Caudate and putamen medium\u2010sized spiny projection neurons (<jats:styled-content style=\"fixed-case\">SPN<\/jats:styled-content>s) most severely degenerate in <jats:styled-content style=\"fixed-case\">HD<\/jats:styled-content>. However, it is unclear why mutant huntingtin protein (<jats:styled-content style=\"fixed-case\">mHTT<\/jats:styled-content>) is preferentially toxic to these neurons or why symptoms manifest only relatively late in life. <jats:styled-content style=\"fixed-case\">mHTT<\/jats:styled-content> interacts with numerous neuronal proteins. Likewise, multiple <jats:styled-content style=\"fixed-case\">SPN<\/jats:styled-content> cellular processes have been described as altered in various <jats:styled-content style=\"fixed-case\">HD<\/jats:styled-content> models. Among these, altered neuronal Ca<jats:sup>2+<\/jats:sup> influx and intracellular Ca<jats:sup>2+<\/jats:sup> handling feature prominently and are addressed here. Specifically, we focus on extrasynaptic <jats:styled-content style=\"fixed-case\">NMDA<\/jats:styled-content>\u2010type glutamate receptors, endoplasmic reticulum <jats:styled-content style=\"fixed-case\">IP<\/jats:styled-content>3 receptors, and mitochondria. As <jats:styled-content style=\"fixed-case\">mHTT<\/jats:styled-content> is expressed throughout development, compensatory processes will likely be mounted to mitigate any deleterious effects. Although some compensations can lessen <jats:styled-content style=\"fixed-case\">mHTT<\/jats:styled-content>'s disruptive effects, others\u2014such as upregulation of the <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>\u2010refilling store\u2010operated Ca<jats:sup>2+<\/jats:sup> channel response\u2014contribute to pathogenesis. A causation\u2010based approach is therefore necessary to decipher the complex sequence of events linking <jats:styled-content style=\"fixed-case\">mHTT<\/jats:styled-content> to neurodegeneration, and to design rational therapeutic interventions. With this in mind, we highlight evidence, or lack thereof, that the above alterations in Ca<jats:sup>2+<\/jats:sup> handling occur early in the disease process, clearly interact with <jats:styled-content style=\"fixed-case\">mHTT<\/jats:styled-content>, and show disease\u2010modifying potential when reversed in animals.<\/jats:p>","DOI":"10.1111\/cns.12817","type":"journal-article","created":{"date-parts":[[2018,2,10]],"date-time":"2018-02-10T04:24:42Z","timestamp":1518236682000},"page":"301-310","source":"Crossref","is-referenced-by-count":41,"title":["Cause or compensation?\u2014Altered neuronal Ca<sup>2+<\/sup> handling in Huntington's disease"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0143-4391","authenticated-orcid":false,"given":"James P.","family":"Mackay","sequence":"first","affiliation":[{"name":"Department of Psychiatry Djavad Mowafaghian Centre for Brain Health University of British Columbia  Vancouver British Columbia 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