Parkin implicated in sporadic Parkinson's disease

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798 http://neurology.thelancet.com Vol 4 December 2005 Although parkin protein has been implicated in familial forms of Parkinson’s disease (PD), its role in sporadic disease is uncertain. But research now suggests that the protein’s inactivation could contribute to sporadic PD. Some patients with familial PD carry a mutation in PARK2, the gene encoding parkin. This mutation makes the protein, which normally tags other proteins for degradation, unable to function, and patients show a substantial loss of catecholaminergic neurons in the substantia nigra and locus coeruleus. Matthew LaVoie (Brigham and Women’s Hospital, Massachusetts, USA) thinks that a similar mechanism may be at work in sporadic PD. His team treated rodent dopaminergic neuronal cells with dopamine and showed that the endogenous parkin protein became insoluble (Nat Med 2005; published online Oct 16. DOI:10.1038/nm1314). The added dopamine binds irreversibly to the parkin protein and blocks its function. The team reasoned that if a similar scenario happens in vivo, it could trigger the demise of dopaminergic substantia-nigra cells and cause sporadic PD. So they looked at postmortem brain material from patients with sporadic PD. The team compared caudate nucleus, which is served by the dopamine-rich substantia nigra, with dopamine-poor cortex tissue and showed that there was more insoluble parkin protein in the caudate. “This indirectly backs up the tissue culture data”, says LaVoie, “although there is no direct evidence here that the changes in solubility in the human brain are brought about by dopamine.” LaVoie thinks increases in dopamine or other factors, such as oxidative stress, could be lowering parkin solubility and so quashing its function. Other factors may be at work, agrees Mark Cookson (National Institute on Aging, Massachusetts, USA). “If dopamine causally contributes to cell loss then it’s likely to be one factor among many”, he says. But if dopamine is the culprit, then it presents a strange paradox. Substantia-nigra cells are especially vulnerable to cell death in Parkinson’s disease. But it’s the dopamine, via its action on parkin, which may trigger cell death. Dopamine, it seems, may be a double-edged sword. The team also looked at parkin in healthy control brains, and found catechol-modified parkin in the substantia nigra, but not elsewhere. Dopamine’s attack on parkin could be one of many predisposing factors to developing sporadic PD, says LaVoie. The suggestion that dopamine contributes to neuronal cell death in sporadic PD may raise concerns about treating patients with dopaminergic therapies, such as levodopa. But LaVoie thinks the treatment is still the best option. “Although L-dopa could be a problem in principle, by the time patients present to their neurologist, much of the cell loss in the substantia nigra will have already occurred”, he says. The neurons that are left will be pretty resilient to any adverse effects of dopamine.