Neuromelanin activates microglia and induces degeneration of dopaminergic neurons: implications for progression of Parkinson's disease.
In Parkinson's disease (PD), there is a progressive loss of neuromelanin (NM)-containing dopamine 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 phagocytized and degraded by microglia within minutes in vitro, extracellular NM particles induce microglial activation and ensuing production of superoxide, nitric oxide, 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, a microglial integrin receptor involved in the initiation of phagocytosis. Neuronal loss was also attenuated with microglia derived from mice deficient in phagocytic oxidase, a subunit of NADPH oxidase, that is responsible for superoxide and H₂O₂ production, or apocynin, an NADPH oxidase inhibitor. In vivo, NM injected into rat SN produces microgliosis and a loss of tyrosine hydroxylase 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.
Zhang
Wei
W
Department of Neurology, Beijing Tiantan Hospital, Beijing 100050, China.
Phillips
Kester
K
Wielgus
Albert R
AR
Liu
Jie
J
Albertini
Alberto
A
Zucca
Fabio A
FA
Faust
Rudolph
R
Qian
Steven Y
SY
Miller
David S
DS
Chignell
Colin F
CF
Wilson
Belinda
B
Jackson-Lewis
Vernice
V
Przedborski
Serge
S
Joset
Danielle
D
Loike
John
J
Hong
Jau-Shyong
JS
Sulzer
David
D
Zecca
Luigi
L
D000818:Animals; D018450:Disease Progression; D004298:Dopamine; D005260:Female; D006801:Humans; D008543:Melanins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344
D008543:Melanins; C014121:neuromelanin; D004298:Dopamine