RESUMO
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.
Assuntos
Envelhecimento , Modelos Animais de Doenças , Técnicas de Transferência de Genes , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Transtornos Parkinsonianos/genética , Fatores Etários , Envelhecimento/genética , Animais , Corpo Estriado/química , Corpo Estriado/metabolismo , Vetores Genéticos/administração & dosagem , Vetores Genéticos/uso terapêutico , Fator Neurotrófico Derivado de Linhagem de Célula Glial/administração & dosagem , Fator Neurotrófico Derivado de Linhagem de Célula Glial/biossíntese , Lentivirus/genética , Macaca mulatta , Masculino , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/prevenção & controle , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/genéticaRESUMO
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.