title: Caffeine and adenosine A(2A) receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado-Joseph disease.
abstract: OBJECTIVE
  Machado-Joseph disease (MJD) is a neurodegenerative disorder associated with an abnormal CAG expansion, which translates into an expanded polyglutamine tract within ataxin-3. There is no therapy to prevent or modify disease progression. Because caffeine (a nonselective adenosine receptor antagonist) and selective adenosine A2A receptor (A2A R) blockade alleviate neurodegeneration in different brain diseases, namely at early stages of another polyglutamine-related disorder such as Huntington's disease, we now tested their ability to control MJD-associated neurodegeneration.
  
  
  METHODS
  MJD was modeled by transducing the striatum of male adult C57Bl/6 mice with lentiviral vectors encoding mutant ataxin-3 in one hemisphere and wild-type ataxin-3 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.
  
  
  RESULTS
  Mutant ataxin-3 caused an evolving neuronal dysfunction (loss of DARPP-32 staining) leading to neurodegeneration (cresyl violet and neuronal nuclei staining) associated with increased number of mutant ataxin-3 inclusions in the basal ganglia. Notably, mutant ataxin-3 triggered early synaptotoxicity (decreased synaptophysin and microtubule-associated protein-2 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 A2A R inactivation (knockout).
  
  
  CONCLUSIONS
  Our findings provide a demonstration that synaptotoxicity and gliosis are precocious events in MJD and that caffeine and A2A R inactivation decrease MJD-associated striatal pathology, which paves the way to consider A2A Rs as novel therapeutic targets to manage MJD.
authors.affiliation: CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Nélio
authors.initials: N
authors.lastname: Gonçalves
authors.forename: Ana T
authors.initials: AT
authors.lastname: Simões
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.forename: Luís Pereira
authors.initials: LP
authors.lastname: de Almeida
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000067699:Ataxin-3; D039481:CD11b Antigen / Q000378:metabolism; D002110:Caffeine / Q000008:administration & dosage*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005822:Genetic Vectors / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D016086:Lentivirus / Q000235:genetics; D017827:Machado-Joseph Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D058915:Purinergic P1 Receptor Antagonists / Q000008:administration & dosage*; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics; D016708:Synaptophysin / Q000378:metabolism; D013997:Time Factors; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D039481:CD11b Antigen; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D012097:Repressor Proteins; D016708:Synaptophysin; D002110:Caffeine; C092341:ATXN3 protein, human; D000067699:Ataxin-3