Ability to delay neuropathological events associated with astrocytic MAO-B increase in a Parkinsonian mouse model: Implications for early intervention on disease progression
Research highlights
►Monoamine Oxidase-B mouse model serves as a novel tool to understand ROS mediated PD pathogenesis. ►Inducible expression of the MAO-B in-vivo allows us to study the exact timing of events. ►MAOB inhibitors and antioxidant drug therapies may be beneficial in preventing disease progression if given early.
Introduction
Monoamine oxidase B (MAO-B) is found in the brain primarily in non-neuronal cells such as astrocytes and radial glia [20], [40], [41]. Age-related increases in its levels have been suggested to play a role in neurodegeneration associated with PD [9], [10], [20], [31], [33]. This is believed to be as a consequence of increased oxidative stress; substrate oxidation by the enzyme is accompanied stoichiometrically by the reduction of oxygen to H2O2 [5], [39]. We previously demonstrated that elevations in astrocytic MAO-B levels in an inducible transgenic mouse model results in a selective loss of dopaminergic SN neurons and that severity of this loss was age-dependent [22]. Cell loss was accompanied by increased oxidative stress and selective inhibition of mitochondrial CI activity, all key features of human Parkinson's disease (PD). Reversing MAO-B induction after 14 days was not sufficient to reverse any of the observed effects when examined 2 weeks later. However, what is not clear from our earlier studies is whether reversing the MAO-B increase at earlier time points would be sufficient to prevent subsequent events or the mechanisms involved. We set out in this current set of studies to investigate the exact timing of events and whether reversal of MAO-B induction at earlier time points was capable of halting or delaying the observed neuropathological progression.
Section snippets
Induction of astrocytic MAO-B levels via dox feeding and impact of dox removal
Dox-inducible astrocytic MAO-B expressing transgenics were generated in the C57Bl/6 background as previously described [22]. Mice were housed according to standard animal care protocols, fed ad libitum, kept on a 12-h light/dark cycle, and maintained in a pathogen-free environment in the Buck Institute Vivarium. Astroglial-specific transgene expression was induced by feeding adult (3–4 months old) males doxycycline at 0.5 g/kg/day provided in pre-mixed Purina chow (Research Diets) for the
Astrocytic MAO-B increase results in subsequent increases in ROS, CI inhibition, and neurodegeneration which could be reversed via dox removal (DR) at days 3–5
Approximately 10–15% of nerve terminals in the striatum (ST) originate from SN dopaminergic neurons [25], [26], [29]. Enrichment of striatal dopaminergic nerve terminal (synaptosomal) populations therefore allows us to measure the impact of astrocytic MAO-B induction directly within dopaminergic nigrostriatal neurons at various time points on both ROS levels and CI activity [22]. ROS levels were measured in isolated ST dopaminergic versus nondopaminergic synaptosomes 3 h following injection of
Discussion
Increased brain MAO-B levels have been hypothesized to play a role in neuropathies associated with PD [4], [5], [15], [23], [27], [42]. It was recently reported that rasagaline (Azilect), a selective irreversible inhibitor of MAO-B, resulted in a delay in disease development in patients who initiated drug treatment at the earlier stages which is consistent with a neuroprotective effect (although this is confounded by the mild improvements and questions about differences with drug dosage). It is
Acknowledgments
These studies were funded by R01 NS045615 (JKA) and a grant from the National Parkinson's Foundation (JKM).
References (43)
- et al.
The relationships between aging, monoamine oxidase, striatal dopamine and the effects of MPTP in C57BL/6 mice: a critical reassessment
Brain Res.
(1992) - et al.
Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease
Neuron
(2003) - et al.
Oxidative alpha-ketoglutarate dehydrogenase inhibition via subtle elevations in monoamine oxidase B levels results in loss of spare respiratory capacity: implications for Parkinson's disease
J. Biol. Chem.
(2003) - et al.
Assessment of mitochondrial oxidative phosphorylation in patient muscle biopsies, lymphoblasts, and transmitochondrial cell lines
Methods Enzymol
(1996) - et al.
Dopamine induces ERK activation in renal epithelial cells through H2O2 produced by monoamine oxidase
Kidney Int.
(2001) - et al.
Localization of distinct monoamine oxidase A and monoamine oxidase B cell populations in human brainstem
Neuroscience
(1988) - et al.
Uncoupling protein-2 is critical for nigral dopamine cell survival in a mouse model of Parkinson's disease
J. Neurosci.
(2005) - et al.
Striatal subregional 6-[18F]fluoro-l-dopa uptake in early Parkinson's disease: a two-year follow-up study
Mov. Disord.
(2006) - et al.
Inducible alterations of glutathione levels in adult dopaminergic midbrain neurons result in nigrostriatal degeneration
J. Neurosci.
(2007) The pathobiology of Parkinson's disease: biochemical aspects of dopamine neuron senescence
J. Neural Transm. Suppl.
(1983)
Parkinson disease: a new link between monoamine oxidase and mitochondrial electron flow
Proc. Nat. Acad. Sci. U.S.A.
Association of a polymorphism in intron 13 of the monoamine oxidase B gene with Parkinson disease
Am. J. Med. Genet.
Endogenous oxidized indoles share inhibitory potency against [3H]isatin binding in rat brain
J. Neural Transm. Suppl.
Ageing and Parkinson's disease: substantia nigra regional selectivity
Brain
The effect of age on the activity and molecular properties of human brain monoamine oxidase
J. Neural Transm.
Pharmacology of selegiline
Neurology
Case-control study of dopamine transporter-1, monoamine oxidase-B, and catechol-O-methyl transferase polymorphisms in Parkinson's disease
Mov. Disord.
Orobuccal dyskinesia associated with trihexyphenidyl therapy in a patient with Parkinson's disease
Mov. Disord.
MAOB intron 13 and COMT codon 158 polymorphisms, cigarette smoking, and the risk of PD
Neurology
An allelic association study of monoamine oxidase B in Parkinson's disease
Ann. Neurol.
Green tea polyphenol (−) -epigallocatechin-3-gallate promotes the rapid protein kinase C- and proteasome-mediated degradation of Bad: implications for neuroprotection
J. Neurochem.
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