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Doktorsavhandling vid Karolinska Institutet

McCormack, Alison

The non-human primate as a model of human Parkinsonism

Fredagen den 27 januari 2006, kl. 9.15.
Seminarierummet, Neurotec, Novum, (nås via Neurotecs huvudentré, plan5).

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ISBN: 91-7140-624-7

Diss: 06:24

Abstract:

The motor deficits seen in Parkinson’s disease (PD) are the result of a loss of catecholaminergic neurons from the substantia nigra (SN) and the associated loss of striatal dopamine. Clinical signs become evident once striatal dopamine levels decline by at least 70-80% and nigral cell numbers by 40%, and worsen with increased duration of the disease. Typically, onset is at around 60 years with increased prevalence with advancing age. Aging is the only unequivocal risk factor for PD, and it has been hypothesized that PD is an accelerated form of this process. In the present study age-related changes in the nigrostriatal system were examined in the non-human primate. Stereological counts showed no change in the total number of dopaminergic nigral neurons with aging when neurons were identified by a combination of dopaminergic markers. However, a decline was noted in number of tyrosine hydroxylase-immunoreactive neurons that was paralleled by an increase in neuromelanin pigmentation with advancing age. Striatal dopamine levels were also significantly lower in old monkeys as compared to young animals (-25% in the putamen and –20% in the caudate), suggesting that nigral neurons undergo a shift in phenotype during aging that may contribute to functional decreases in the striatum.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a toxin that selectively targets dopaminergic neurons, resulting in a similar pattern of nigrostriatal damage and behavioral motor changes to those seen in PD. In non-human primates an inverse relationship exists between age and the amount of MPTP needed to generate the same degree of motor deficits. Here the direct effects of a single dose of MPTP on animals of different ages were examined. An age-related sensitivity to MPTP was seen, with significantly greater dopaminergic cell loss in the SN of old (50%) vs. young (25%) animals and more marked striatal dopamine depletion in old as compared to young monkeys (30% and 70% depletion in young and old animals respectively). The presence of neuromelanin also conferred increased vulnerability to MPTP-induced neurodegeneration, a feature seen in the neurodegenerative processes in PD.

One of the classic pathological hallmarks of PD, the Lewy body, is a cytoplasmic inclusion, a major constituent of which is the protein alpha-synuclein. The relationship between alpha-synuclein and neurodegeneration was examined by administering a single dose of MPTP. In control monkeys, alpha-synuclein immunostaining was only present in fibers of the SN. One week after MPTP when only a small degree of nigral cell loss was seen, alpha-synuclein mRNA levels were increased. alpha-Synuclein protein levels in the SN were also slightly increased by western blotting, but immunoreactivity was still only present in the neuropil. One month after MPTP, a 40% loss of nigral neurons was noted along with a shift in the distribution of alpha-synuclein to the cell bodies of the remaining dopaminergic neurons. Therefore in this model, increased alpha-synuclein levels were not consistently associated with neurotoxicity, but rather were seen in surviving neurons.

Long-term use of levodopa therapy in PD is associated with abnormal involuntary movements, levodopa-induced dyskinesias (LIDs), which can also be induced in the non-human primate. Presynaptic damage to striatal dopaminergic terminals reduces the DA storage capacity, making buffering of elevated levels of DA present during levodopa therapy difficult. Here, the extent of nigrostriatal damage effected the time of onset of LID. After priming by a first cycle of levodopa, a second cycle of levodopa treatment resulted in quicker onset of LIDs in severely lesioned monkeys as compared to more moderately lesioned ones, suggesting that the severity of nigrostriatal injury enhances the sensitivity of animals to subsequent levodopa exposures. Further support for a role for presynaptic damage in LID came from findings in methamphetamine-treated animals subsequently treated with levodopa in which significantly more severe LIDs were noted as compared to unlesioned levodopa-treated animals.

The roles of aging and neuromelanin in increased vulnerability of pigmented populations of neurons and the pathological role of alpha-synuclein in PD may be all clarified by the use of MPTP in the non-human primate. This model is also important in relation to studies examining the therapeutic treatment with levodopa in patients with PD.

Keywords: Parkinson’s disease; substantia nigra; aging; neuromelanin; MPTP; alpha-synuclein; levodopa; dyskinesia; methamphetamine

List of papers

	Aging of the nigrostriatal system in the squirrel monkey. McCormack AL, Di Monte DA, Delfani K, Irwin I, DeLanney LE, Langston WJ, Janson AM J Comp Neurol, 2004; 471(4): 387-95
	Alpha-synuclein expression in the substantia nigra of MPTP-lesioned non-human primates. Purisai MG, McCormack AL, Langston WJ, Johnston LC, Di Monte DA Neurobiol Dis, 2005; 20(3): 898-906. Epub 2005 Jul 11
	Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model. Di Monte DA, McCormack AL, Petzinger G, Janson AM, Quik M, Langston WJ Mov Disord, 2000; 15(3): 459-66
	Methamphetamine enhances levodopa-induced dyskinesias in the squirrel monkey. McCormack AL, Togaski DM, Quik M, Langston JW, Di Monte DA Manuscript

Doktorsavhandling vid Karolinska Institutet

McCormack, Alison

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