Does smoking reduce the risk of Parkinson's disease through stimulation of the ubiquitin-proteasome system?

Parkinson's disease is a neurodegenerative condition characterized by tremor, rigidity, bradykinesia, and postural instability. Smoking is an inverse risk factor for Parkinson's disease, although the mechanism for this apparent neuroprotection is not definitively established. Smoking consistently upregulates nicotinic acetylcholine receptor levels in various brain regions known to be involved in Parkinson's disease. The ubiquitin-proteasome system--the system that tags and removes unwanted, misfolded, or damaged proteins from cells--regulates nicotinic receptor levels. The ubiquitin-proteasome system has also been implicated in Parkinson's disease, with aberrant activity identified in both sporadic and familial forms of the disease. The involvement of the ubiquitin-proteasome system in nicotinic receptor regulation and Parkinson's disease pathology suggests a link between the two, which forms the basis of the present hypothesis. Specifically, this paper considers the hypothesis that smoking reduces the risk of Parkinson's disease through the upregulation of nicotinic cholinergic receptors in key brain regions involved in Parkinson's disease. This receptor upregulation is hypothesized to increase activity of the ubiquitin-proteasome system, which is believed to prevent neurodegeneration caused by the accumulation of misfolded or damaged proteins or other consequences of inadequate protein sequestration and/or degradation. This hypothesis is supported by evidence documenting the upregulation of nicotinic receptors in the brains of smokers, neuroprotective effects of nicotine, reduced activity of the ubiquitin-proteasome in Parkinson's disease, and increased activity of the ubiquitin-proteasome system in animals exposed to chronic nicotine. Additional research is needed to test several predictions of the hypothesis, including increased activity of the ubiquitin-proteasome system in key brain regions of smokers.