MAO-B Elevation in Mouse Brain Astrocytes Results in Parkinson's Pathology

Abstract

Age-related increases in monoamine oxidase B (MAO-B) may contribute to neurodegeneration associated with Parkinson's disease (PD). The MAO-B inhibitor deprenyl, a long-standing antiparkinsonian therapy, is currently used clinically in concert with the dopamine precursor L-DOPA. Clinical studies suggesting that deprenyl treatment alone is not protective against PD associated mortality were targeted to symptomatic patients. However, dopamine loss is at least 60% by the time PD is symptomatically detectable, therefore lack of effect of MAO-B inhibition in these patients does not negate a role for MAO-B in pre-symptomatic dopaminergic loss. In order to directly evaluate the role of age-related elevations in astroglial MAO-B in the early initiation or progression of PD, we created genetically engineered transgenic mice in which MAO-B levels could be specifically induced within astroglia in adult animals. Elevated astrocytic MAO-B mimicking age related increase resulted in specific, selective and progressive loss of dopaminergic neurons in the substantia nigra (SN), the same subset of neurons primarily impacted in the human condition. This was accompanied by other PD-related alterations including selective decreases in mitochondrial complex I activity and increased mitochondrial oxidative stress. Along with a global astrogliosis, we observed local microglial activation within the SN. These pathologies correlated with decreased locomotor activity. Importantly, these events occurred even in the absence of the PD-inducing neurotoxin MPTP. Our data demonstrates that elevation of murine astrocytic MAO-B by itself can induce several phenotypes of PD, signifying that MAO-B could be directly involved in multiple aspects of disease neuropathology. Mechanistically this may involve increases in membrane permeant H2O2 which can oxidize dopamine within dopaminergic neurons to dopaminochrome which, via interaction with mitochondrial complex I, can result in increased mitochondrial superoxide. Our inducible astrocytic MAO-B transgenic provides a novel model for exploring pathways involved in initiation and progression of several key features associated with PD pathology and for therapeutic drug testing.

Evaluation of the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to toxic pyridinium cations by monoamine oxidase (MAO) enzymes and its use to search for new MAO inhibitors and protective agents

“…MAO isozymes are good targets for antidepressants (MAO-A inhibitors) and neuroprotective drugs (MAO-B inhibitors) 1,45 . The oxidation of biogenic amines and neurotransmitters by MAO produces reactive oxygen species (ROS) 2,16 , and the elevation of MAO-B is associated with an increased susceptibility to neurodegeneration 6 . In addition, MAO may oxidize neurotoxins like MPTP and analogs to directly-acting toxic pyridinium metabolites (MPDP + and MPP + ) 10,11,15,17,37,46 ( Figure 1).…”

“…MPTP is deactivated by Cytochrome P450 (CYP) enzymes through N-demethylation and aromatic hydroxilation and the metabolic balance between MAO and CYP influences its toxic outcome 15 . The activity of MAO-B increases with age 1 , and its elevation in the brain may result in an increased risk of neurodegeneration 6 . Thus, inhibition of MAO may afford neuroprotection through a lower production of reactive oxygen species (ROS) and aldehydes, as well as a diminished activation of toxins such as MPTP and/ or related substances 2,6,16,17 .…”

“…The activity of MAO-B increases with age 1 , and its elevation in the brain may result in an increased risk of neurodegeneration 6 . Thus, inhibition of MAO may afford neuroprotection through a lower production of reactive oxygen species (ROS) and aldehydes, as well as a diminished activation of toxins such as MPTP and/ or related substances 2,6,16,17 . Therefore, studying MAO enzymes and finding new MAO inhibitors as purported neuroprotectants is a subject of current interest in drug discovery 1,[18][19][20][21][22][23][24][25][26] .…”

“…Inhibition of MAO may protect against oxidative stress and thereof the identification of novel MAO inhibitors is a subject of interest in drug discovery 1,5,6 . Parkinson's disease (PD) is a neurodegenerative disease associated with a progressive loss of dopaminergic neurons in the substantia nigra.…”

Genes involved in the development of Parkinson

“…Induction of MAO-B in astrocytes of adult transgenic mice leads to selective and progressive loss of dopaminergic neurons [52]. Dopamine oxidation products (dopamine quinones), can also contribute to neurodegeneration [53].…”