Mecanismos de degeneración neuronal dopaminérgica inducidos por la administración subaguda y crónica de MPTP a monos Cynomolgus

Resumen

We assessed by histochemical analysis the presence of degenerating neurons in the substantia nigra pars compacta (SNpc) and ventral tegmental area (VTA) of monkeys treated subacutely and chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and sacrificed at different survival times. We also evaluated the changes of α-synuclein (α-syn) expression, α-syn aggregation and the alteration in proteasomal activity within the nigral dopaminergic cells of these animals. Firstly, we found that only those monkeys treated subacutelly with MPTP and with the shortest survival time (1 week) displayed dopaminergic neurons suffering a degenerative process in the SNpc. In contrast, animals with the greatest survival time, independently of the MPTP dose, did not show any degenerating neuron. Secondly, we observed that subacute MPTP treated monkeys, but not chronic MPTP monkeys, showed a significant increased number of apoptotic cells in the SNpc. Apoptotic cells exhibited morphological features and histological markers indicative of glial cells, whereas no evidence of neuronal apoptosis was observed. Thirdly, our data showed that subacute and chronic MPTP administration provokes α-syn overexpression in the nigral dopaminergic cells as demonstrated by enhanced intensity of α-syn immunoreactivity in the SNpc neurons and by the increased percentage of dopaminergic cells expressing α-syn. We also found that in some neurons cytoplasmatic α-syn accumulation was the aggregated (insoluble) form of this protein. Changes either in α-syn expression or distribution were not observed in other catecholaminergic neurons such as locus coeruleus cells. Finally, decreased levels of 20S-α4 proteasomal subunit protein within nigral dopaminergic neurons were observed after subacute MPTP intoxication that was further decreased in chronic MPTP monkeys. Taken together, our results indicate that MPTP treatment produced a non apoptotic cell death of dopaminergic cells and the activation of the apoptotic cascade in glial cells. More importantly, we failed to demonstrate the existence of a delayed neurodegenerative process in the dopaminergic neurons after concluding MPTP injection thus, casting doubt on the validity of the ¿progressive model¿ created by repeated MPTP administration to monkeys. Finally, our data suggests that a sequence of pathogenic events starting with mitochondrial complex I inhibition, followed by up-regulation and aggregation of α-syn and proteasomal dysfunction might lead to nigral dopaminergic degeneration.