. Parkin deficiency increases vulnerability to inflammation-related nigral degeneration. J Neurosci. 2008 Oct 22;28(43):10825-34. PubMed.


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  1. The etiopathogenesis of sporadic Parkinson disease (PD) is only poorly understood. Over the past decade, several genes have been linked to monogenic familial variants of PD, which can provide insight into the pathomechanisms and allow the generation of PD-specific animal models. Mutations in the parkin gene (PARK2), encoding a E3 ubiquitin ligase, are responsible for the majority of autosomal recessive parkinsonism. Parkin knockout mice show some minor alterations in dopaminergic neurotransmission; however, they do not display overt degeneration of the nigrostriatal pathway. The authors of this study therefore reasoned that an additional "hit" is needed to induce loss of dopaminergic neurons in parkin knockout mice, consistent with the idea that genetic and environmental factors play a role in the pathogenesis of PD.

    Using a paradigm of chronic inflammation triggered by serial low-dose intraperitoneal LPS injections, the authors first show that this regimen induces a specific neuroinflammatory response in brain regions which are affected in early stages of PD: the midbrain and olfactory bulb. In contrast to wild-type mice, parkin knockout mice developed fine-locomotor deficits in response to the inflammatory stimulus. Remarkably, systemic LPS treatment increased the vulnerability to nigral dopaminergic neuron loss in parkin knockout mice, while the profile and extent of the midbrain neuroinflammatory response in wild-type and parkin knockout mice was similar.

    The fact that nigral neuron loss was not accompanied by striatal pathology, such as fiber degeneration and dopamine depletion, appears puzzling at first glance. On the other hand, this observation might indicate that inflammatory responses are regulated differently in the substantia nigra and striatum, explaining the high vulnerability of nigral neurons to inflammatory stimuli, such as TNF. In line with the current study is the recent finding that parkin has a permissive effect on NFκB signaling. It will now be interesting to address the question of how neuroinflammation and nigral degeneration are linked mechanistically and whether neuroinflammation plays a pathogenic role specifically in patients with pathogenic parkin mutations.

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