Neurology Central

Lewy bodies hold clues to molecular mechanisms in Parkinson’s

Parkinson’s disease is known to affect over 1 million patients in the US alone, its cause its typically unknown and a cure for this progressive disorder has remained elusive.

The hallmark sign of Parkinson’s disease is the intraneuronal accumulation and progressive spreading of Lewy bodies, formed mainly through the accumulation of alpha-synuclein. Extent of Lewy body clumps and the severity of Parkinson’s disease have been well correlated, leading to wide acceptance of the hypothesis that these inclusions accelerate the disease process. Therefore, research to identify and develop molecules capable of decreasing or even halting formation of these alpha-synuclein-containing toxic inclusions may be beneficial for Parkinson’s disease patients.

With this in mind, a research team led by Assia Shiseva (Wayne State University School of Medicine, MI) has made breakthrough developments in a new molecular mechanism which may be able to melt these pathological clumps. Shisheva’s laboratory have spent over a decade looking at the cellular functions of the PIKfyve and Sac3 enzymes, in addition to one accessory protein, ArPIKFyve. The groups previous work has revealed that when not bound and protected by ArPIKfyve, Sac3 is prone to rapid demise inside the cell. In addition, the double ArPIKfyve—Sac3 protein complex constitutes part of a larger triple assembly which also incorporates the PIKfyve enzyme. This triple complex is responsible for the production and turnover of a rare phospholipid molecule which controls traffic of membranes towards the cell digestive system.

The relationship between Sac3 mutations and neurodegeneration in humans has thus far remained a mystery, with human mutations in PIKfyve only currently associated with a relatively benign disease of the cornea. This knowledge led Shisheva and colleagues to believe that the double ArPIKfyve—Sac3 complex has separate functions in the brain. Thus, they sought to identify brain-specific proteins that physically interact with the double complex ArPIKfyve—Sac3.

In their recent paper published in the Journal of Biological Chemistry, the team characterized a novel interaction partner of the ArPIKfyve—Sac3 complex in the brain. “We uncovered that the ArPIKfyve—Sac3 complex binds Synphilin-1, a protein already implicated in the pathogenesis of Parkinson’s disease through its interaction with alpha-synuclein,” explained Shisheva. “As alpha-synuclein, Synphilin-1 is also entrapped in the abnormal Lewy body deposits. Our study revealed that the ArPIKfyve—Sac3 complex is an effective inhibitor of aggregate formation by Synphilin-1.”

The team also observed that excessive Sac3 levels cause protein self-aggregation and further facilitate Synphilin-1 clumping. It is now believed that levels of Sac3 that are either too low or disproportionally high may precipitate Parkinson’s disease.

The ArPIKfyve—Sac3 complex could, according to Shisheva, shift Synphilin-1 distribution from a form of multiple aggregates towards the soluble form. Thus, ArPIKfyve—Sac3 based therapies may one day prove beneficial for the reduction of neurodegeneration in Parkinson’s.

Sources: Ikonomov O, Sbrissa D, Compton L, et al. The protein complex of neurodegeneration-related phosphoinositide phosphatase Sac3 and ArPIKfyve binds the Lewy-body-associated Synphilin-1 preventing its aggregation. J. Biol. Chem. doi: 10.1074/jbc.M115.669929. (2015) ( Epub ahead of print); Wayne State University University Press Release