Research Brief: α-synuclein Spoils the Neural Neighborhood

Aggregates of α-synuclein are the principal component of Lewy bodies, neuronal inclusions found in Parkinson and other neurodegenerative diseases—and they get around. Cells normally keep their α-synuclein problems to themselves, but when more accumulates than they can handle, they may release the protein into the extracellular space. Unfortunately, dumping trash in your neighbor’s yard is rarely a good idea. A report posted online in PNAS July 27 shows that the nearby cells can pick up α-synuclein jetsam, helping the toxic protein spread from cell to cell across the brain. The results may help explain why tissues transplanted into people with Parkinson’s eventually succumb to the disease (see ARF related news story; Kordower et al., 2008 and Li et al., 2008), and they beef up the idea that aggregation-prone proteins can be transmitted in the brain much like prions.

The work was a joint effort between the laboratories of Seung-Jae Lee of Konkuk University in Seoul, South Korea, and Eliezer Masliah of the University of California at San Diego. The joint first authors were Paula Desplats from the University of California and He-Jin Lee from Konkuk University. PD Online Research coverage carries commentary on the discovery and an interview with Lee.

The work parallels discoveries of aggregate migration in other neurodegenerative diseases. Aβ (see ARF related news story on Eisele et al., 2009), tau (see ARF related news story on Clavaguera et al., 2009; and ARF related news story on Frost et al., 2009), and polyglutamine peptides (Ren et al., 2009) all spread across the brain. Such transport may be a common theme, wrote Mathias Jucker of the University of Tbingen in Germany, in an e-mail to ARF: I am sure there are more to come. Jucker was not involved in the current study. How relevant this is for the pathogenesis of the disease is still open, he noted.

Lee and colleagues had already discovered that neurons can exocytose (Lee et al., 2005) and endocytose (Lee et al., 2008) α-synuclein. In the current work, they put the two together to show that toxic forms of the protein move from cell to cell, seeding new aggregates as they go. In co-cultures of donor neurons expressing human α-synuclein and acceptor stem cells lacking it, it took only a day for nearly half of the acceptors to exhibit α-synuclein accumulation. In human α-synuclein-expressing mice that received stem cell grafts, the transplanted cells also picked up the protein, similar to what may have happened to cell grafts in human clinical trials for PD (see ARF related news story). One month after the mice received transplants, 15 percent of grafted cells contained the human protein, and a few hosted Lewy-like inclusion bodies as well. Acceptor neurons exhibited symptoms of apoptosis, including fragmented nuclei and caspase 3 activation, that control cells not exposed to α-synuclein did not.

This is an interesting and well-done study showing that pathogenic α-synuclein can be transferred from cell to cell both in vitro and in vivo, wrote Lary Walker of Emory University in Atlanta, Georgia, in an e-mail to ARF. It should come as no surprise that grafted cells in Parkinson’s patients succumb to synucleinopathy, he added. Transplantation of healthy cells into such a diseased brain is rather like trying to rebuild a burned house while the fire is still raging. He noted that the experimental systems reported in the paper should be useful for analyzing the problem and looking for therapeutics to circumvent it.

Masliah is thinking along similar lines. We want to develop cells or grafts that would be resistant to these toxic oligomers, he said. Such graft cells might be oblivious to their neighbor’s garbage.

Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A. 2009 Jul 27. Abstract

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