Dumpster Diving: Picking through cellular trash leads to new parkin substrate

Mary Beckman

Key Words: Parkinson's disease • Lewy body • parkin • synphilin-1 • synuclein • immunoprecipitation

Abstract: Just as Hollywood garbage cans expose the sordid lives of the stars, cellular trash might reveal clues about illicit activities that lead to Parkinson's disease. A protein called parkin marks damaged proteins for disposal. Mutations in parkin cause a rare type of Parkinson's disease--one that afflicts adolescents--so scientists have hoped that its targets might reveal the disorder's underlying pathology. Although a few substrates have been identified, they don't explain the path from a parkin mutation to the trembling, rigid patient.

Now, researchers have found another protein that parkin tags. Furthermore, they've shown that the mutation responsible for the juvenile-onset disease prevents protein aggregates known as Lewy bodies from forming. These structures dot the brain cells of people with late-onset disease: those who succumb at age 60 or above. The new results point to a common pathology for the different classes of the disorder.

Dawson and colleagues wondered whether parkin interacts with either of two proteins---synuclein and synphilin-1--that are known to bind to each other and to accumulate in Parkinson's-disease-specific Lewy bodies. The researchers produced parkin along with each single protein in human cells. They found that normal parkin grips synphilin-1--but not -synuclein--and attaches a small protein called ubiquitin to it; that "scarlet letter" dooms synphilin-1 to destruction. In contrast, the juvenile-onset mutations cripple parkin's ability to tag synphilin-1. The group's results also suggest that all three proteins conspire to create Lewy body-like structures--at least in cell culture: Coproduction of the normal version of parkin with both synphilin-1 and -synuclein triggers the formation of cytoplasmic protein clumps. But when the defective form of parkin is produced with synphilin-1 and -synuclein, no clumps form. This observation is consistent with a curious distinction of the parkin-linked juvenile form of Parkinson's disease: the absence of Lewy bodies.

Until now, synphilin-1 has taken a back seat to -synuclein, famous for its link to familial forms of the disease in humans. But synphilin-1's association with two proteins---synuclein and now parkin--that independently cause disease throws it into the researchers' spotlight. Harmful -synuclein mutations might, like defective parkin, prevent synphilin-1's annihilation, instead letting it wreak havoc on the cell. Furthermore, the new work suggests that patients with parkin-linked disease lack Lewy bodies because the aberrant form of parkin prevents these structures from forming. Perhaps normal parkin sweeps up poison proteins--maybe -synuclein, although other candidates exist--and deposits them in Lewy bodies in order to render them harmless. Late-onset disease might occur when the toxins eventually overwhelm the cell's broom and dustpan. In the early-onset version, parkin's compromised ability to keep house could allow the corrupt protein to poison brain cells more quickly. Researchers' ability to recreate this scene in cell culture might help them take out the cellular trash.

--Mary Beckman

K. K. K. Chung, Y. Zhang, K. L. Lim, Y. Tanaka, H. Huang, J. Gao, C. A. Ross, V. L. Dawson, T. M. Dawson, Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: Implications for Lewy-body formation in Parkinson disease. Nature Medicine 7, 1144-1150 (2001). [Abstract] [Full Text]

Citation: M. Beckman, Dumpster Diving: Picking through cellular trash leads to new parkin substrate. Science's SAGE KE (17 October 2001), http://sageke.sciencemag.org/cgi/content/abstract/sageke;2001/3/nw9