Involvement of dopaminergic neuronal cystatin C in neuronal injury‐induced microglial activation and neurotoxicity

Abstract

J. Neurochem. (2012) 122, 752–763. Abstract Factors released from injured dopaminergic (DA) neurons may trigger microglial activation and set in motion a vicious cycle of neuronal injury and inflammation that fuels progressive DA neurodegeneration in Parkinson’s disease. In this study, using proteomic and immunoblotting analysis, we detected elevated levels of cystatin C in conditioned media (CM) from 1‐methyl‐4‐phenylpyridinium and dieldrin‐injured rat DA neuronal cells. Immunodepletion of cystatin C significantly reduced the ability of DA neuronal CM to induce activation of rat microglial cells as determined by up‐regulation of inducible nitric oxide synthase, production of free radicals and release of proinflammatory cytokines as well as activated microglia‐mediated DA neurotoxicity. Treatment of the cystatin C‐containing CM with enzymes that remove O‐ and sialic acid‐, but not N‐linked carbohydrate moieties markedly reduced the ability of the DA neuronal CM to activate microglia. Taken together, these results suggest that DA neuronal cystatin C plays a role in the neuronal injury‐induced microglial activation and neurotoxicity. These findings from the rat DA neuron‐microglia in vitro model may help guide continued investigation to define the precise role of cystatin C in the complex interplay among neurons and glia in the pathogenesis of Parkinson’s disease.

Cerebrospinal fluid markers including trefoil factor 3 are associated with neurodegeneration in amyloid-positive individuals

“…33 Conversely, increased CysC immunoreactivity is seen in specific neuronal population in AD suggesting a role in neurodegeneration; 33 and in dopaminergic neurons, CysC has been shown to have a role in neuronal injury-mediated microglial activation and neurotoxicity. 34 Our finding of a positive relationship between rates of atrophy and CysC, in individuals in whom amyloid deposition has already occurred, could therefore be explained in terms of a harmful neuroinflammatory response which results in neuronal damage. VEGF, abundantly expressed in the CNS, has roles in modulation of angiogenesis, vascular remodelling, repair, permeability and inflammation, 35 and is involved in microglial chemotaxis perhaps reflecting an early response to amyloid deposition.…”

In vivo reprogramming of astrocytes to neuroblasts in the adult brain

“…YFP + cells were widely distributed throughout the brain. Although endogenous Cst3 is expressed in certain neurons under pathological conditions 37–39 , neither neurons nor oligodendrocytes were traced by YFP in the striatum of adult Cst3–CreER T2 ;Rosa–YFP mice (Fig. 5a–d).…”

Cystatin C is a disease‐associated protein subject to multiple regulation

“…Indeed electrical induction of a status epilepticus causes upregulation of Cst C expression in rat neurons and glia 97 . In addition, persistent environmental toxicants, like dieldrin, and neurotoxin MPP (1‐methy1‐4phenyl‐1,2,3,6‐tetrahydropyridine), were also reported to injure dopaminergic neurons and stimulate their secretion of Cst C for microglia activation and neurotoxicity 98 …”