Human myeloperoxidase (hMPO) is expressed in neurons in the substantia nigra in Parkinson’s disease and in the hMPO-α-synuclein-A53T mouse model, correlating with increased nitration and aggregation of α-synuclein and exacerbation of motor impairment.

Human myeloperoxidase (hMPO) is expressed in neurons in the substantia nigra in Parkinson’s disease and in the hMPO-α-synuclein-A53T mouse model, correlating with increased nitration and aggregation of α-synuclein and exacerbation of motor impairment.

Publication date: Jun 05, 2019

α-Synuclein (αSyn) is central to the neuropathology of Parkinson’s disease (PD) due to its propensity for misfolding and aggregation into neurotoxic oligomers. Nitration/oxidation of αSyn leads to dityrosine crosslinking and aggregation. Myeloperoxidase (MPO) is an oxidant-generating enzyme implicated in neurodegenerative diseases. In the present work we have examined the impact of MPO in PD through analysis of postmortem PD brain and in a novel animal model in which we crossed a transgenic mouse expressing the human MPO (hMPO) gene to a mouse expressing human αSyn -A53T mutant (A53T) (hMPO-A53T). Surprisingly, our results show that in PD substantia nigra, the hMPO gene is expressed in neurons containing aggregates of nitrated αSyn as well as MPO-specific HOCl-modified epitopes. In our hMPO-A53T mouse model, we also saw hMPO expression in neurons but not mouse MPO. In the mouse model, hMPO was expressed in neurons colocalizing with nitrated αSyn, carbamylated lysine, nitrotyrosine, as well as HOCl-modified epitopes/proteins. RNAscope in situ hybridization confirmed hMPO mRNA expression in neurons. Interestingly, the hMPO protein expressed in hMPO-A53T brain is primarily the precursor proMPO, which enters the secretory pathway potentially resulting in interneuronal transmission of MPO and oxidative species. Importantly, the hMPO-A53T mouse model, when compared to the A53T model, exhibited significant exacerbation of motor impairment on rotating rods, balance beams, and wire hang tests. Further, hMPO expression in the A53T model resulted in earlier onset of end stage paralysis. Interestingly, there was a high concentration of αSyn aggregates in the stratum lacunosum moleculare of hippocampal CA2 region, which has been associated in humans with accumulation of αSyn pathology and neural atrophy in dementia with Lewy bodies. This accumulation of αSyn aggregates in CA2 was associated with markers of endoplasmic reticulum (ER) stress and the unfolded protein response with expression of activating transcription factor 4 (ATF4), C/EBP homologous protein (CHOP), MPO, and cleaved caspase-3. Together these findings suggest that MPO plays an important role in nitrative and oxidative damage that contributes to αSyn pathology in synucleinopathies.

Concepts Keywords
Atrophy Branches of biology
Brain Lewy body dementia
CA2 Proteins
Caspase 3 Organ systems
CHOP Peripheral membrane proteins
Crosslinking Neuropathology
Dementia Neurological disorders
Endoplasmic Reticulum Parkinson’s disease
Enzyme Alpha-synuclein
Epitopes Synucleinopathy
ER Stress Neurodegeneration
Hippocampal Hybridization
HOCl
Homologous
Hybridization
Lewy Bodies
Lysine
Misfolding
MRNA
Mutant
Myeloperoxidase
Neurodegenerative Diseases
Neurons
Neuropathology
Neurotoxic
Nitrated
Nitration
Oligomers
Oxidant
Oxidation
Oxidative Damage
Oxidative Species
Paralysis
Parkinson
Pathology
Postmortem
Secretory Pathway
Substantia Nigra
Transcription Factor
Transgenic

Semantics

Type Source Name
drug DRUGBANK Hypochlorous acid
disease DOID synucleinopathies
pathway BSID Oxidative Damage
gene UNIPROT DDIT3
gene UNIPROT SH3D19
gene UNIPROT EBP
gene UNIPROT GLB1
gene UNIPROT ATF4
disease DOID dementia with Lewy bodies
disease MESH atrophy
gene UNIPROT CA2
disease MESH paralysis
gene UNIPROT ZNF699
gene UNIPROT WIPF2
drug DRUGBANK Isoxaflutole
drug DRUGBANK L-Lysine
gene UNIPROT IMPACT
pathway BSID Neurodegenerative Diseases
disease MESH neurodegenerative diseases
gene UNIPROT MPO
gene UNIPROT SYNM
gene UNIPROT FYN

Similar

Original Article

Leave a Comment

Your email address will not be published. Required fields are marked *