Neuromelanin Activates Microglia and Induces Degeneration of Dopaminergic Neurons: Implications for Progression of Parkinson’s Disease

Abstract

In Parkinson's disease (PD), there is a progressive loss of neuromelanin (NM)-containing dopamine (DA) neurons in substantia nigra (SN) which is associated with microgliosis and presence of extracellular NM. Herein, we have investigated the interplay between microglia and human NM on the degeneration of SN dopaminergic neurons. Although NM particles are phagocytised and degraded by microglia within minutes in vitro, extracellular NM particles induce microglial activation and ensuing production of superoxide, nitric oxide (NO), hydrogen peroxide (H2O2), and pro-inflammatory factors. Furthermore, NM produces, in a microglia-depended manner, neurodegeneration in primary ventral midbrain cultures. Neurodegeneration was effectively attenuated with microglia derived from mice deficient in macrophage antigen complex-1 (Mac-1), a microglial integrin receptor involved in the initiation of phagocytosis. Neuronal loss was also attenuated with microglia derived from mice deficient in phagocytic oxidase (PHOX), a subunit of NADPH oxidase, that is responsible for superoxide and H2O2 production, or apocyanin, a NADPH oxidase inhibitor. In vivo, NM injected into rat SN produces microgliosis and a loss of tyrosine hydroxylase (TH) neurons. Thus, these results show that extracellular NM can activate microglia, which in turn, may induce dopaminergic neurodegeneration in PD. Our study may have far-reaching implications, both pathogenic and therapeutic.

The neuroprotective effects of apocynin

“…Accordingly, recent studies using genetic deletion of gp91 phox have shown that microglial activation and NADPH-oxidase-derived free radicals play major roles in the toxicity of a variety of compounds leading to dopaminergic neuronal death (75,76). Apocynin has been used effectively to inhibit neurotoxicity for 6-OHDA (77), MPTP/MPP + (75,78), neuromelanin (79) and environmental neurotoxins such as paraquat (80,81), rotenone (82) and formyl-methionyl-leucyl-phenylalanine (83) in vitro with dopaminergic neurons, neuron-glia co-cultures or slice culture preparations. Most importantly, apocynin is also beneficial when used in vivo in different animal models of PD; preadministration of apocynin protects against paraquat-induced dopaminergic cell death in mice (80) and 6-OHDA-induced neurodegeneration in rats (84).…”

Microglial endocytosis and transglutaminases

“…In neuronal/glial mixed culture, nanomolar Aβ, which was not directly toxic to neurons but activated microglia, induced neuronal death by microglial phagocytosis [3]. It has been reported also in PD model that microglial phagocytosis might be involved in neuronal loss [48][49][50]. Taken together, the control of microglial phagocytosis might be important for neuronal survival in neurodegenerative diseases and the regulations of TG2 expression and TG enzyme activity might be targets of the mechanism to control microglial phagocytosis.…”

Iron chelation in the treatment of neurodegenerative diseases

“…Notably, quantitative susceptibility mapping appears to be more sensitive for iron estimation in the SNpc than R2* transverse relaxivity measurement [120][121][122][123][124]. At the microscopic level, iron deposits in the SNpc are associated with neuromelanin granules in dopaminergic neurons [125], Lewy bodies [32], and activated microglial cells [126]. Enhanced diffuse iron staining is also apparent in the neuropil of the SN [127].…”