22 December 2002. One of the hallmarks of Parkinson's disease (PD) is the accumulation of Lewy bodies, intracellular inclusions containing proteins that have been ear-marked for degradation. Why these proteins are not destroyed in PD neurons is unclear, but a report in this week's Neuron strengthens the link between PD and the proteasome (see also ARF related news story and see ARF related story).
The proteasome, a cellular version of the wood chipper—sucking proteins in one end and spitting peptides out the other—is an essential element in the cycle of protein synthesis and degradation. Principle author Mark Cookson at the National Institute on Aging, Bethesda, Maryland, together with colleagues at the Mayo Clinic Jacksonville, Florida, and Loyola University Medical Center, Maywood, Illinois, show that inhibitors of the proteasome are far more detrimental to cells expressing mutants of the protein α-synuclein that have been implicated in the etiology of PD. The inhibitor MG132, for example, kills about 30 percent of wild-type neurons, but for cells with the α-synuclein mutants A30P and A53T, this attrition jumps to 70 and 50 percent, respectively. The authors obtained similar results using another proteasome inhibitor, lactacystin.
First author Leonard Petrucelli et al. go on to show that inhibition of the proteasome can be relieved with the protein parkin, mutants of which are linked to early-onset, familial forms of PD. Wild type parkin, the authors show, protects against MG132 and lactacystin. Furthermore, Petrucelli et al. show that parkin can completely eliminate the hypersensitivity to proteasome tampering that occurs in α-synuclein expressing cells, thus connecting parkin and synuclein with proteasome function.
Not all neurons are equally affected by proteasome inhibition. The authors reveal that dopaminergic cells—those expressing tyrosine hydroxylase—are much more susceptible to the inhibitors and to mutant synuclein isoforms, indicating, yet again, that it may be no coincidence that these neurons are the ones devastated by Parkinson's.—Tom Fagan
Petrucelli L, O'Farrell C, Lockhart PJ, Baptista M, Kehoe K, Vink L, Choi P, Wolozin B, Farrer M, Hardy J, Cookson MR. Parkin protects against the toxicity associated with mutant a-synuclein: proteasome dysfunction selectively affects catecholaminergic Neurons. Neuron 2002 December 19;36:1007-1019. Abstract