AAV-mediated expression of Bcl-xL or XIAP fails to induce neuronal resistance against quinolinic acid-induced striatal lesioning.
Apoptotic mechanisms have been proposed to contribute to the selective loss of medium spiny striatal projection neurons in Huntington's disease (HD). This raises the question as to whether enhancing the expression of anti-apoptotic factors in vulnerable striatal projection neurons can reduce their susceptibility to neurotoxic processes occurring in the HD brain. In this study AAV 1/2 vectors encoding either the anti-apoptotic factor Bcl-xL or XIAP were used to transduce striatal neurons prior to an intrastriatal injection of the excitotoxic glutamate analogue quinolinic acid (QA). AAV 1/2 vector treated rats were observed in behavioural tests undertaken to assess whether anti-apoptotic factor expression provided amelioration of motor function impairment following unilateral QA-induced striatal lesioning. AAV-XIAP treated rats displayed complete amelioration of an ipsilateral forelimb use bias relative to control animals. However, neither AAV-XIAP nor AAV-Bcl-xL treated rats demonstrated an improvement in sensorimotor neglect compared to control animals. Furthermore, we did not observe a significant reduction of QA-induced pathology in assessed neuronal populations of the basal ganglia. These results indicate that sole enhancement of XIAP or Bcl-xL is not sufficient to counteract QA-induced excitotoxic insult of striatal neurons.
Kells
Adrian P
AP
Department of Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, New Zealand. a.kells@auckland.ac.nz
Connor
Bronwen
B
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001930:Brain Injuries / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D003342:Corpus Striatum / Q000473:pathology*; D000229:Dependovirus / Q000235:genetics; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D008297:Male; D016253:Microscopy, Immunoelectron / Q000379:methods; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D017378:Quinolinic Acid; D051381:Rats; D017208:Rats, Wistar; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism*
C494813:Bcl2l1 protein, rat; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; D017378:Quinolinic Acid