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

• Published in: Brain research Vol. 1395; pp. 94 - 107
• Main Authors: Khodr, Christina E, Sapru, Mohan K, Pedapati, Jyothi, Han, Ye, West, Neva C, Kells, Adrian P, Bankiewicz, Krystof S, Bohn, Martha C
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 13-06-2011; Elsevier
• Subjects: Adeno-associated virus; Adult and adolescent clinical studies; adverse effects; alpha-Synuclein - genetics; alpha-Synuclein - physiology; animal models; Animals; Biological and medical sciences; brain; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Dependovirus - genetics; Disease Models, Animal; dopamine; Dopamine - physiology; Forelimb - physiopathology; gene silencing; Gene Silencing - physiology; Gene therapy; Genetic Therapy - methods; Genetic Vectors - pharmacology; Genetic Vectors - toxicity; HEK293 Cells; Humans; injection site; long term effects; luciferase; Male; Medical sciences; Neurodegeneration; Neurology; neurons; Neurons - metabolism; Neurons - pathology; Organic mental disorders. Neuropsychology; Parkinson disease; Parkinsonian Disorders - genetics; Parkinsonian Disorders - physiopathology; Parkinsonian Disorders - therapy; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Sprague-Dawley; RNA; RNA, Small Interfering - biosynthesis; RNA, Small Interfering - genetics; RNA, Small Interfering - toxicity; RNAi; Substantia nigra; therapeutics; toxicity; Treatment Outcome; Tyrosine hydroxylase; RNAi; Tyrosine hydroxylase; Gene therapy; Neurodegeneration; Substantia nigra; Animal model; Rat; Toxicity; Central nervous system; Parkinson disease; Tyrosine 3-monooxygenase; Encephalon; Gene; Degenerative disease; Degeneration; Behavior; α-synuclein; Nervous system diseases; Enzyme; Rodentia; Cerebral disorder; Vertebrata; Mammalia; Locus niger; Animal; Central nervous system disease; Dopaminergic neuron; Oxidoreductases; Extrapyramidal syndrome
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2011.04.036

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.