An alpha-synuclein AAV gene silencing vector ameliorates a behavioral deficit in a rat model of Parkinson's disease, but displays toxicity in dopamine neurons

Christina E. Khodr, Mohan K. Sapru, Jyothi Pedapati, Ye Han, Neva C. West, Adrian P. Kells, Krystof S. Bankiewicz, Martha C. Bohn

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

Effects of silencing ectopically expressed hSNCA in rat substantia nigra (SN) were examined as a novel therapeutic approach to Parkinson's disease (PD). AAV-hSNCA with or without an AAV harboring a short-hairpin (sh)RNA targeting hSNCA or luciferase was injected into one SN. At 9 weeks, hSNCA-expressing rats had reduced SN dopamine (DA) neurons and exhibited a forelimb deficit. AAV-shRNA-SNCA silenced hSNCA and protected against the forelimb deficit. However, AAV-shRNA-SNCA also led to DA neuron loss suggesting undesirable effects of chronic shRNA expression. Effects on nigrostriatal-projecting neurons were examined using a retrograde tract tracer. Loss of striatal-projecting DA neurons was evident in the vector injection site, whereas DA neurons outside this site were lost in hSNCA-expressing rats, but not in hSNCA-silenced rats. These observations suggest that high levels of shRNA-SNCA were toxic to DA neurons, while neighboring neurons exposed to lower levels were protected by hSNCA gene silencing. Also, data collected on DA levels suggest that neurons other than or in addition to nigrostriatal DA neurons contributed to protection of forelimb use. Our observations suggest that while hSNCA gene silencing in DA neurons holds promise as a novel PD therapy, further development of silencing technology is required.

Original languageEnglish (US)
Pages (from-to)94-107
Number of pages14
JournalBrain research
Volume1395
DOIs
StatePublished - Jun 13 2011

Funding

This study was supported by the Department of Defense Neurotoxicology Program ( NO06079001 ) and NIH grants ( NS31957 and NS054989 to MCB and T32 NS041234 to CEK), the Harry F and Elaine M Chaddick Foundation and the Medical Research Institute Council of Children's Memorial Hospital. Support from the Chicago Biomedical Consortium and the Illinois Excellence in Academic Medicine to the CMRC Viral Vector Core is acknowledged. The technical assistance of Jianping Xie, Xue Song Wang, David George and Brian Corstange (Children's Memorial Research Center) is appreciated. The authors thank James Surmeier (Northwestern University) for his insightful comments on the manuscript. MCB and MKS hold a European patent on this technology and have a pending U.S. patent application.

Keywords

  • Gene therapy
  • Neurodegeneration
  • RNAi
  • Substantia nigra
  • Tyrosine hydroxylase

ASJC Scopus subject areas

  • Clinical Neurology
  • Molecular Biology
  • General Neuroscience
  • Developmental Biology

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