A Clique's Undoing: Cousins of aggregating proteins prevent the Lewy body gang from getting together

Abstract

Molecular gangs wreak havoc in many neurodegenerative diseases. For example, a protein called α-synuclein bands into dense, spherical clods called Lewy bodies that injure the brains of people with Parkinson's and other so-called Lewy body diseases (LBDs). These sinister gatherings presumably lead to symptoms associated with LBDs such as memory loss, hallucinations, and loss of motor control (see Posner Case Study and Andersen Review). According to new research, β-synuclein--a relative of α-synuclein--might prevent the troublesome protein from misbehaving: In mice, it keeps the α-synuclein clique from hanging together and blocks disease progression. The findings hint at a possible new contributor to LBDs: Perhaps in some people faulty β-synucleins arise and let the α-synucleins congregate. α- and β-synuclein differ in at least one important respect: The latter lacks a sticky portion that makes α-synucleins cling to each other. In some afflictions that involve protein mobs, molecules that resemble the ones that glob up can prevent this destructive process. Hashimoto and colleagues wondered whether β-synuclein might similarly prevent α-synuclein from coalescing. The researchers had previously engineered mice that produce human α-synuclein and exhibit Parkinson-like symptoms. They mated these animals with mice that produce human β-synuclein to create a strain that carries both proteins. These mice, unlike the ones that manufacture only α-synuclein, maintained their balance on a rotating rod as well as normal ones did. In addition, they contained healthier neurons and fewer protein clumps--the mouse equivalent of human Lewy bodies--than did the mice that make α-synuclein alone. The researchers also gathered clues about how β-synuclein might counteract α-synuclein's destructive behavior. In mixtures from mouse brain and kidney cells, α- and β-synuclein bind to each other. Furthermore, observations of human synucleins produced by bacteria revealed that α-synuclein clustering declines as β-synuclein abundance increases--at least in a test tube. Together, the results suggest that β-synuclein handcuffs its gang-prone cousins, effectively keeping the troublemakers apart. Although the results suggest that β-synuclein-based therapy might hinder Lewy body formation, several questions hang over the current work. Despite multiple attempts, other researchers have failed to generate a mouse with Parkinson-like symptoms. Different strain backgrounds might explain this discrepancy, so it's possible that the mice used in this study might harbor a genetic co-conspirator in LBDs; if so, the current work might not apply to otherwise normal animals, although the mice could help identify the relevant gene or genes. Moreover, mice produce their own synuclein proteins, and the study does not account for possible interactions between the mouse and human versions. Still, the research suggests that boosting concentrations of mob-busting proteins might thwart disruptive assemblies of their relatives. Such an approach holds promise for treating LBDs as well as other neurodegenerative diseases that arise from similar molecular throngs. --Katharine Miller M. Hashimoto, E. Rockenstein, M. Mante, M. Mallory, E. Masliah, β-synuclein inhibits α-synuclein aggregation: A possible role as an anti-Parkinsonian factor. Neuron 32 , 213-223 (2001). [Abstract] [Full Text]