Protein family review

This in an extract of a protein family review which first appeared in GenomeBiology, and is reproduced by permission of the publisher, BioMedCentral Ltd.

Authors:

Julia M George

Department of Cell and Structural Biology, University of Illinois, Urbana, IL 61801, USA.

Correspondence:

Julia George.

Email:

j-george@uiuc.edu

Read the full article

Subscribers to GenomeBiology may view the full version of this review article online at www.genomebiology.com

Published:

20 December 2001

The synucleins

Summary

Synucleins are small, soluble proteins expressed primarily in neural tissue and in certain tumors. The family includes three known proteins: α-synuclein, β-synuclein, and γ-synuclein. All synucleins have in common a highly conserved α-helical lipid-binding motif with similarity to the class-A₂ lipid-binding domains of the exchangeable apolipoproteins. Synuclein family members are not found outside vertebrates, although they have some conserved structural similarity with plant 'late-embryo-abundant' proteins. The α- and β-synuclein proteins are found primarily in brain tissue, where they are seen mainly in presynaptic terminals. The γ-synuclein protein is found primarily in the peripheral nervous system and retina, but its expression in breast tumors is a marker for tumor progression. Normal cellular functions have not been determined for any of the synuclein proteins, although some data suggest a role in the regulation of membrane stability and/or turnover. Mutations in α-synuclein are associated with rare familial cases of early-onset Parkinson's disease, and the protein accumulates abnormally in Parkinson's disease, Alzheimer's disease, and several other neurodegenerative illnesses. The current challenge is to understand the normal cellular function of these proteins and how they might contribute to the development of human disease.

Frontiers

The association of synucleins with human disease has focused a great deal of interest on this protein family. The question of what the synucleins do still remains, however. Most of the experimental evidence available with regard to function is gleaned from experiments with α-synuclein, but the conservation of an extended, class-A2 amphipathic α helix comprising more than half of each of the protein sequences indicates a common biochemical mechanism among all synucleins, probably involving lipid binding. Perrin et al. [35] report irreversible multimerization of α-, β-, and γ-synuclein upon exposure to polyunsaturated phospholipid species, cellular membrane components that are the most susceptible to oxidative damage. This specific interaction might serve to protect these vulnerable lipids from damage or to scavenge damaged lipids and target them for turnover. Paxinou et al. [32] also noted recently that α-synuclein is degraded, at least in part, by the lysosome, suggesting a role for α-synuclein in the autophagocytic clearance of damaged cellular organelles. Thus, it is tempting to speculate that the synucleins help to maintain cellular membrane integrity. But much work remains to be done to elucidate the normal cellular functions of these unusually conserved proteins and to determine how they contribute to diverse disease processes spanning neurodegenerative disease and cancer.

Comparison of the amphipathic α-helical domains of α-synuclein and related proteins