ABSTRACT
This study assessed the potential for functional and anatomical recovery of the diseased aged primate nigrostriatal system, in response to trophic factor gene transfer. Aged rhesus monkeys received a single intracarotid infusion of MPTP, followed one week later by MRI-guided stereotaxic intrastriatal and intranigral injections of lentiviral vectors encoding for glial derived neurotrophic factor (lenti-GDNF) or beta-galactosidase (lenti-LacZ). Functional analysis revealed that the lenti-GDNF, but not lenti-LacZ treated monkeys displayed behavioral improvements that were associated with increased fluorodopa uptake in the striatum ipsilateral to lenti-GDNF treatment. GDNF ELISA of striatal brain samples confirmed increased GDNF expression in lenti-GDNF treated aged animals that correlated with functional improvements and preserved nigrostriatal dopaminergic markers. Our results indicate that the aged primate brain challenged by MPTP administration has the potential to respond to trophic factor delivery and that the degree of neuroprotection depends on GDNF levels.
Subject(s)
Aging , Disease Models, Animal , Gene Transfer Techniques , Glial Cell Line-Derived Neurotrophic Factor/genetics , Parkinsonian Disorders/genetics , Age Factors , Aging/genetics , Animals , Corpus Striatum/chemistry , Corpus Striatum/metabolism , Genetic Vectors/administration & dosage , Genetic Vectors/therapeutic use , Glial Cell Line-Derived Neurotrophic Factor/administration & dosage , Glial Cell Line-Derived Neurotrophic Factor/biosynthesis , Lentivirus/genetics , Macaca mulatta , Male , Parkinsonian Disorders/physiopathology , Parkinsonian Disorders/prevention & control , Psychomotor Performance/drug effects , Psychomotor Performance/physiology , Recovery of Function/drug effects , Recovery of Function/geneticsABSTRACT
A nucleotide sequence is reported for RNA-3, the smallest of the three major RNA species found in particles of raspberry bushy dwaft virus (RBDV). The sequence of 946 nucleotides contains a single large open reading frame which encodes an Mr 30,509 polypeptide. In vitro translation of RNA-3 yielded an Mr 30,000 product that reacted specifically with antiserum to RBDV particles and we conclude that the amino acid sequence deduced from the sequence of RNA-3 is that of the RBDV coat protein, or an immediate precursor of it. No affinities were detected by comparing the nucleotide sequence of RNA-3 with the sequences of other plant viruses.
