Characterization of a novel interaction between presenilin-1 and monoamine oxidase-A
The enzyme monoamine oxidase (MAO) is linked to mental disorders such as depression and neurodegenerative diseases. Our laboratory has recently demonstrated that increases in calcium (Ca²⁺) can enhance MAO activity and that this might contribute to Alzheimer disease (AD). AD has been linked to gain-of-function mutations in the presenilin-1 (PS-1) protein that not only promote the generation of the toxic amyloid-β peptide, but that also alter intracellular Ca²⁺ availability. Radioenzymatic MAO assays were used to demonstrate that over-expression of different AD-related PS-1 mutant proteins, i.e. Y115H, ΔEx9 and M146V, in hippocampal-derived HT-22 cells alter either basal and/or Ca²⁺-sensitive MAO-A activity. The effects of PS-1 mutant proteins on the availability of intracellular Ca²⁺ are not consistent suggesting that this may not be the primary means of regulating MAO activity. The sensitivity of MAO to Ca²⁺ was also demonstrated in cortical (both MAO-A and MAO-B responded to Ca²⁺) and cerebellar (only MAO-A responded to Ca²⁺) samples from transgenic mice overexpressing the PS-1 (M146V) mutation. These changes in MAO coincided with changes in the availability of the neurotransmitters dopamine, noradrenaline and serotonin in the cerebellum, but not in the cortex, and reflect the known regional differences in neurotransmitter regulation. Immunoprecipitation studies and the observed increase in MAO-A activity following in vitro chemical inhibition of the γ-secretase complex (comprising several proteins including PS-1) support the notion that PS-1 constitutively associates with MAO-A. These effects on Ca²⁺-sensitive MAO function could contribute to AD-related pathology and could also contribute to the depression often associated with AD.
Calcium, Alzheimer disease, Presenilin-1, Monoamine oxidase
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