A2A receptor knockout worsens survival and motor behaviour in a transgenic mouse model of Huntington's disease.
Huntington's disease (HD) is a progressive neurodegenerative genetic disorder that leads to motor, cognitive, and psychiatric disturbances. The primary neuropathological hallmark is atrophy of the striatum. HD preferentially affects efferent striato-pallidal neurons that express enkephalin as well as dopamine D2 and A(2A) adenosine receptors (A(2A)Rs). Expression and function of A(2A)Rs are altered in HD but, despite being an important modulator of the striato-pallidal function, the subsequent pathophysiological consequence of such changes remains unclear. Whether blockade of A(2A)Rs is of therapeutic interest in HD remains ill-defined. In the present work, we aimed to determine the pathophysiological consequences of genetic deletion of A(2A)Rs in HD by crossing A(2A)R knockout mice with the N171-82Q HD transgenic model. Our data demonstrate that knockout of A(2A)Rs moderately but significantly worsens motor performances and survival of N171-82Q mice and leads to a decrease in striatal enkephalin expression. These results support that early and chronic blockade of A(2A)Rs might not be beneficial in HD.
IRIBHM, Université Libre de Bruxelles, Brussels, Belgium.
Stéphane
S
Mievis
David
D
Blum
Catherine
C
Ledent
D000818:Animals; D004745:Enkephalins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics; D043705:Receptor, Adenosine A2A / Q000172:deficiency* / Q000235:genetics*; D015996:Survival Rate
D004745:Enkephalins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D043705:Receptor, Adenosine A2A