Elsevier

Neurobiology of Disease

Volume 20, Issue 1, October 2005, Pages 93-103
Neurobiology of Disease

Unraveling substantia nigra sequential gene expression in a progressive MPTP-lesioned macaque model of Parkinson's disease

https://doi.org/10.1016/j.nbd.2005.02.005Get rights and content

Abstract

Taking advantage of a progressive nonhuman primate model mimicking Parkinson's disease (PD) evolution, we monitored transcriptional fluctuations in the substantia nigra using Affymetrix microarrays in control (normal), saline-treated (normal), 6 days-treated (asymptomatic with 20% cell loss), 12 days-treated (asymptomatic with 40% cell loss) and 25 days-treated animals (fully parkinsonian with 85% cell loss). Two statistical methods were used to ascertain the regulation and real-time quantitative PCR was used to confirm their regulation. Surprisingly, the number of deregulated transcripts is limited at all time points and five clusters exhibiting different profiles were defined using a hierarchical clustering algorithm. Such profiles are likely to represent activation/deactivation of mechanisms of different nature. We briefly speculate about (i) the existence of yet unknown compensatory mechanisms is unraveled, (ii) the putative triggering of a developmental program in the mature brain in reaction to progressing degeneration and finally, (iii) the activation of mechanisms leading eventually to death in final stage. These data should help development of new therapeutic approaches either aimed at enhancing existing compensatory mechanisms or at protecting dopamine neurons.

Introduction

Parkinson's disease (PD) is a progressive neurodegenerative disorder of which the principal pathological characteristic is the loss of dopamine (DA) neurons of the substantia nigra pars compacta (SNc) (Hassler, 1938). Parkinsonian signs appear when dopaminergic neuronal death exceeds a critical threshold: 70–80% of striatal nerve terminals and 50–60% of SNc pericarya (Bernheimer et al., 1973). The nature of the etiology of the process underlying clinical deterioration remains unknown, but PD is characterized by its progressiveness (Hoehn and Yahr, 1967). Although cell death processes and compensatory mechanisms, responsible for the gradual appearance and worsening of clinical signs, are better understood through the identification of genetic mutations responsible for familial cases of PD (Dawson and Dawson, 2003b) and the use of neurotoxin-based animal models (Berg et al., 2001, Blum et al., 2001, Dawson and Dawson, 2003a, Giasson and Lee, 2001), our understanding of PD progression remains close to zero.

Indeed, most experimental approaches have ignored the progressive nature of PD and have not taken into account the possibility that cell death mechanisms may vary accordingly to the extent of degeneration. Until recently, it has proved difficult to ascertain both the nature of such a sequence of events and its relationship with any subsequent plastic response of the SN. In the absence of animal models that replicate the progressive degenerative processes and the difficulty of longitudinal studies in man, it has been impossible to investigate such a question of paramount importance. Recently, an animal model of PD, which is able to address these issues, has been developed (Bezard et al., 2003). In this model, repeated administration of low doses of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the nonhuman primate (Macaca fascicularis) initiates a process of neurodegeneration reminiscent of that seen in PD (Bezard et al., 2001c, Bezard et al., 2003). The novelty of the model accrues from the fact that, during the first 13–15 days of the protocol, despite significant dopaminergic loss, symptoms, are not apparent. During this period, several mechanisms compensate for the increasing loss of DA, suppressing the appearance of symptoms (Bezard et al., 1999, Bezard et al., 2001a, Bezard et al., 2001b, Bezard et al., 2001c). The model is thus extremely attractive for defining neural mechanisms, and potential biomarkers, that relate to the progression of PD.

High-density oligonucleotide arrays offer the opportunity to survey the transcriptional profiles of large numbers of genes and allow complex biology especially as it relates to disease processes, making possible the unraveling of the basis of PD progression (Marvanova et al., 2003). In this model-driven study, in contrast to hypothesis-driven experiments, we have taken advantage of our progressive nonhuman primate paradigm to monitor transcriptional fluctuations in the SN using human Affymetrix microarray technology, previously shown to display statistically satisfactory human and macaca cross-hybridization properties (Marvanova et al., 2003).

Section snippets

Animals

Experiments were conducted on twenty-one female cynomolgus monkeys (M. fascicularis, CAS, Beijing, PR China; mean age = 3.0 ± 0.2 years; mean weight = 2.8 ± 0.2 kg). Animals were housed in individual primate cages under controlled conditions of humidity (50 ± 5%), temperature (24 ± 1°C) and light (12h light/12h dark cycles, time lights on 8:00 am), food and water were available ad libitum and animal care was supervised by veterinarians skilled in the healthcare and maintenance of nonhuman

Changes in motor behavior

Changes in motor behavior were fully comparable to those previously reported with this administration protocol (Bezard et al., 2001c). Monkeys at day 6 (D6; n = 5) and day 12 (D12; n = 5) did not exhibit parkinsonian motor symptoms (parkinsonian score of 0 for all animals at both time points; P > 0.5 compared to both control and saline groups). Both the D6 and D12 groups were thus asymptomatic. Monkeys in the day 25 (D25; n = 5) group exhibited parkinsonian motor abnormalities as reflected by

Discussion

The present work relates to the relationship between the transcription changes in the SN and the level of nigrostriatal degeneration in a progressive MPTP-lesioned macaque model of PD. Five clusters can be described as five temporal profiles that are likely to represent activation/deactivation of mechanisms of different nature. We briefly speculate about (i) the existence of yet unknown compensatory mechanisms is unraveled, (ii) the putative triggering of a developmental program in the mature

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