{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:17:39Z","timestamp":1791919059076,"version":"4.3.4"},"reference-count":79,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2013,4,26]],"date-time":"2013-04-26T00:00:00Z","timestamp":1366934400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2013,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Machado\u2013Joseph disease (MJD) is a neurodegenerative disorder associated with an abnormal CAG expansion, which translates into an expanded polyglutamine tract within ataxin\u20103. There is no therapy to prevent or modify disease progression. Because caffeine (a nonselective adenosine receptor antagonist) and selective adenosine A<jats:sub>2A<\/jats:sub> receptor (A<jats:sub>2A<\/jats:sub>R) blockade alleviate neurodegeneration in different brain diseases, namely at early stages of another polyglutamine\u2010related disorder such as Huntington's disease, we now tested their ability to control MJD\u2010associated neurodegeneration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>MJD was modeled by transducing the striatum of male adult C57Bl\/6 mice with lentiviral vectors encoding mutant ataxin\u20103 in one hemisphere and wild\u2010type ataxin\u20103 in the other hemisphere (as internal control). Caffeine (1g\/L) was applied through the drinking water. Mice were killed at different time points (from 2 to 12 weeks) to probe for the appearance of different morphological changes using immunohistochemical analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Mutant ataxin\u20103 caused an evolving neuronal dysfunction (loss of DARPP\u201032 staining) leading to neurodegeneration (cresyl violet and neuronal nuclei staining) associated with increased number of mutant ataxin\u20103 inclusions in the basal ganglia. Notably, mutant ataxin\u20103 triggered early synaptotoxicity (decreased synaptophysin and microtubule\u2010associated protein\u20102 staining) and reactive gliosis (glial fibrillary acidic protein and CD11b staining), which predated neuronal dysfunction and damage. Caffeine reduced the appearance of all these morphological modifications, which were also abrogated in mice with a global A<jats:sub>2A<\/jats:sub>R inactivation (knockout).<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings provide a demonstration that synaptotoxicity and gliosis are precocious events in MJD and that caffeine and A<jats:sub>2A<\/jats:sub>R inactivation decrease MJD\u2010associated striatal pathology, which paves the way to consider A<jats:sub>2A<\/jats:sub>Rs as novel therapeutic targets to manage MJD. 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