Parkin Deficiency Increases Vulnerability to Inflammation-Related Nigral Degeneration

Abstract

The loss of nigral dopaminergic (DA) neurons in idiopathic Parkinson's disease (PD) is believed to result from interactions between genetic susceptibility and environmental factors. Evidence that inflammatory processes modulate PD risk comes from prospective studies that suggest that higher plasma concentrations of a number of proinflammatory cytokines correlate with an increased risk of developing PD and chronic nonsteroidal anti-inflammatory drug regimens reduce the incidence of PD. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient ( parkin؊/؊) mice do not display nigrostriatal pathway degeneration, suggesting that a genetic factor is not sufficient, and an environmental trigger may be needed to cause nigral DA neuron loss. To test the hypothesis that parkin؊/؊ mice require an inflammatory stimulus to develop nigral DA neuron loss, low-dose lipopolysaccaride (LPS) was administered intraperitoneally for prolonged periods. Quantitative real-time PCR and immunofluorescence labeling of inflammatory markers indicated that this systemic LPS treatment regimen triggered persistent neuroinflammation in wild-type and parkin؊/؊ mice. Although inflammatory and oxidative stress responses to the inflammation regimen did not differ significantly between the two genotypes, only parkin؊/؊ mice displayed subtle fine-motor deficits and selective loss of DA neurons in substantia nigra. Therefore, our studies suggest that loss of Parkin function increases the vulnerability of nigral DA neurons to inflammation-related degeneration. This new model of nigral DA neuron loss may enable identification of early biomarkers of degeneration and aid in preclinical screening efforts to identify compounds that can halt or delay the progressive degeneration of the nigrostriatal pathway.

Systemic LPS administration induces brain inflammation but not dopaminergic neuronal death in the substantia nigra

“…Systemic inflammation may convert a subtoxic insult to toxicity, and/or mild toxicity to potent toxicity. Although parkin-deficient mice do not display degeneration of dopaminergic neurons in the SNpc (Goldberg et al, 2003;Itier et al, 2003;Von Coelln et al, 2004;Zhu et al, 2007), long-term systemic treatment with low-dose LPS triggered persistent neuroinflammation and selective loss of dopaminergic neurons (Frank-Cannon et al, 2008). In a murine prion disease model, systemic LPS administration aggravated the extent of neuronal death (Cunningham et al, 2005).…”

Elevated TRAF2/6 expression in Parkinson's disease is caused by the loss of Parkin E3 ligase activity

“…Recently, based on the frequent deletion or mutation in human colon cancer, Parkin has been suggested as a haploinsufficient tumor suppressor gene. 13,14 As chronic inflammation is tightly related with colon cancer as well as PD, 15,16 we examined the biological role of Parkin in the cytokine-induced inflammation response.…”

Role of the Transcription Factor Nrf2 in Parkinson’s Disease: New Insights

“…Moreover, preclinical PD models suggest that inflammation is a driving force in DA neuron loss [37]. This idea is supported by experiments where chronic intraperitoneal injection of bacterial lipopolysaccharide (LPS) elicits a systemic immune response and leads to DA neuron loss and PD pathology in mice [40,41]. This inflammatory model of PD suggest that inflammatory stress can manifest in DA neuron loss likely through infiltration of peripheral leukocytes.…”