Human neuromelanin an endogenous microglial activator for dopaminergic neuron death

Abstract

Substantial evidence indicates that neuroinflammation caused by over-activation of microglial in the substantia nigra is critical in the pathogenesis of dopaminergic neurodegeneration in Parkinson’s disease (PD). Increasing data demonstrates that environmental factors such as rotenone, paraquat play pivotal roles in the death of dopaminergic neurons. Here, potential role and mechanism of neuromelanin (NM), a major endogenous component in dopaminergic neurons of the substantia nigra, on microglial activation and associated dopaminergic neurotoxicity were investigated. Using multiple well-established primary mesencephalic cultures, we tested whether human NM (HNM) could activate microglia, thereby provoking dopaminergic neurodegeneration. The results demonstrated that in primary mesencephalic neuron-glia cultures, HNM caused dopaminergic neuronal damage characterized by the decreased dopamine uptake and reduced numbers and shorted dendrites of dopaminergic neurons. HNM-induced degeneration was relatively selective to dopaminergic neurons since the other types of neurons determined by either gamma-aminobutyric acid uptake and total neuronal numbers after staining showed smaller decrease. We demonstrated that HNM produced modest dopaminergic neurotoxicity in neuron-enriched cultures; in contrast, much greater neurotoxicity was observed in the presence of microglia. HNM-induced microglial activation was shown by morphological changes and production of proinflammatory and neurotoxic factors. These results suggest that HNM, once released from damaged dopaminergic neurons, can be an potent endogenous activator involved in the reactivation of microglia, which may mediate disease progression. Thus, inhibition of reactive microglia can be a useful strategy for PD therapy.

MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration

“…Our results suggest a selective upregulation of neuronal MHC-I, antigen presentation and cytolytic activity that may participate under some physiopathological conditions. It has recently been demonstrated that microglia can be activated by substances released by degenerating neurons in PD, such as α-syn 34,53 or NM 35,52 , and that activated microglia can elicit neurotoxic responses 54–56 . Both NM and α-syn are found extracellularly in the postmortem brain of PD patients 57 , a disorder that features high levels of activated microglia in the SN 33 and high levels of intracellular oxidative stress 39 .…”

Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease

“…Due to its insolubility, the released NM granules could remain for long periods in the extracellular space of the human SN, and provide a source of chronic inflammation: this extraneuronal NM moreover slowly releases to the extracellular milieu the toxic compounds adsorbed into the NM structure. In addition, the extracellular NM particles can be phagocytosed and degraded by activated microglia cells, with the consequence that the toxic compounds and redox active metals previously immobilized into NM can be released, which could further exacerbate microglial activation and neuronal damage, as demonstrated by several in vitro and in vivo models of PD (Zecca et al, 2008c; Zhang et al, 2011, 2013). Consistent with studies reporting an age-related loss of SN pigmented neurons, extraneuronal granules of NM have been reported in the SN of non-diseased elderly subjects in association with microglial activation (Beach et al, 2007).…”

“…In cell culture studies, the treatment of microglia cultures with human NM pigment produces chemotaxis: microglia cells move toward NM granules, actively phagocytose NM granules, and release neurotoxic molecules including tumor-necrosis factor α, interleukin 6, nitric oxide (Wilms et al, 2003) and reactive molecules such as superoxide and hydrogen peroxide (Zhang et al, 2011, 2013). Interestingly, the injection of NM into rat SN causes intense microglia activation and degeneration of DA neurons with a moderate astrocytosis (Zecca et al 2008c; Zhang et al, 2011, 2013).…”

Abordagem para análise proteômica de neurônios contendo neuromelanina na substância negra, isolados por microdissecção a laser

“…Regiões encefálicas contendo células produtoras de neuromelanina: (A) substância negra -mesencéfalo (B) locus coeruleus -ponte (C) formação reticular -bulbo. Modificado de Fedorow et al, 2005 Vários estudos têm sido realizados com o objetivo de compreender melhor o papel da neuromelanina no envelhecimento normal e no processo neurodegenerativo (Lindquist et al, 1987;Fasano et al, 2006;Bisaglia et al, 2009;Zhang et al, 2013). Uma hipótese é a de que a neuromelanina desempenhe um papel protetor, evitando danos de substâncias nocivas como, íons metálicos redox-ativos, toxinas e excesso de catecolaminas citosólicas às células (Zucca et al, 2004;Zucca et al, 2014).…”

“…Uma hipótese é a de que a neuromelanina desempenhe um papel protetor, evitando danos de substâncias nocivas como, íons metálicos redox-ativos, toxinas e excesso de catecolaminas citosólicas às células (Zucca et al, 2004;Zucca et al, 2014). No entanto, também tem sido demonstrado um potencial tóxico para neuromelanina atuando como ativadora da micróglia endógena e, por consequente, causando inflamação (Zhang et al, 2013). Outra hipótese seria de que a neuromelanina em excesso poderia inibir a função do proteassoma (Shamoto-Nagai et al, 2004).…”