Trends in Neurosciences
The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease
Section snippets
Three genes produce similar proteins in the brain
Synuclein proteins were discovered independently by at least four different labs before any sequence data became available in Genbank, thus spawning a profusion of names. The first published report, in 1988, described a protein enriched in the electric organ of the Pacific electric ray (Torpedo californica) and a related sequence found in a rat brain cDNA library[1]. Here, Maroteaux et al. coined the name synuclein on the basis of initial evidence for both synaptic and nuclear localization, but
Apolipoprotein-like structure
A defining feature shared by all synucleins is the presence of a loosely repeated motif throughout the first 93 residues, causing a variation in hydrophobicity1, 5, 16with a strictly conserved periodicity of 11 ([3]). A periodicity of 11 is characteristic of the amphipathic helices of apolipoproteins, and if a helical secondary structure is assumed for this domain in synuclein, a well-ordered amphipathic arrangement of amino acids emerges[3]. Secondary structure rules developed from study of
α synuclein: center of the storm
It is the α gene that has been specifically implicated in PD and AD, and it has been identified and studied in more contexts than its two cousins1, 3, 4, 8, 23, 24. The gene has been mapped to chromosome 4 in humans25, 26, 27, 28, 29. Antibodies have been successfully raised to several parts of the α protein, as summarized in Fig. 1, Fig. 2, but many may also show significant cross-reactivity with the β protein. Human genomic sequences have been examined to determine exon boundaries (Fig. 1,
β synuclein: a carbon-copy of α – almost
β synuclein (PNP-14) was first identified as a brain-specific protein in bovine and rat[5], was then shown to be a phosphoprotein[7], and has recently been detected at low levels in tissues other than brain[32]. Independently, the human β protein was detected (along with α synuclein) by a monoclonal antibody originally raised against paired helical filaments of AD brains, and from this the human sequence was cloned[4] and mapped to chromosome 5 ([29]). The α and β proteins are extremely
γ synuclein: now a link to breast cancer
Synucleins have also been implicated in a non-neural disease from studies of gene products specifically associated with breast cancer. The `breast cancer-specific gene 1' (BCSG1) was identified by a direct-differential cDNA sequencing approach: it was greatly over-represented in cDNA libraries made from human breast cancers versus normal breast tissue[12]. In situ hybridization analyses of sections from 53 breast tumors and controls revealed virtually no detectable expression in normal or
In brain, a role in regulation or support of synaptic plasticity seems likely
α and β (and probably γ) synuclein are enriched at presynaptic terminals, as shown by combined immunocytochemistry and subcellular fractionation studies in songbird[3], rat2, 14, 21 and human brain4, 31. Expression of both α ([24]) and β ([21]) is minimal in the embryonic rat brain. Synuclein does not appear to be a constitutive component of synapses but might be added after initial synaptogenesis: the appearance of synucleins at synaptic specializations in cultured hippocampal cells is delayed
Involvement in AD
In general, the distribution of α synuclein in the brain is very similar to the distribution of brain pathology in AD (2, 31). The principal biochemical component of amyloid plaques in AD is the β-amyloid peptide, but the NAC fragment derived from α synuclein comprises about 10% of the protein that remains insoluble after SDS detergent extraction[8]. It remains possible that additional portions of the synuclein protein are present in amyloid, although an antibody to the C terminus of the
Involvement in PD
Although most cases of PD are sporadic in origin, familial forms do exist, and in the last year linkage was established to an α-synuclein allele in four apparently unrelated families with a highly penetrant form of autosomal dominant, early-onset PD ([23]). The allele was present in ten out of 11 individuals with PD in these families but not in 314 chromosomes from unaffected controls. Absence of linkage to this allele has been established in investigations of other PD-affected patient
Is there a common denominator?
One has to wonder if the pathology in PD or AD (or both) might be only indirectly related to the normal function of the protein. Perhaps it is simply a major constituent of synaptic specializations, where metabolic turnover may be inefficient and the risk of oxidative damage high. Yet it is also possible that the very properties that accelerate amyloid deposition or precipitate Lewy bodies (or support breast cancer) are central to the normal function of the protein. If a common denominator
Acknowledgements
The authors' work was supported by NIH grants NS-25742 and AG-13762. We thank Brad Hyman and Mike Irizarry for many useful suggestions; Richard Perrin and Benjamin Gantner for help in sequence analyses; and the members of our labs for many valuable discussions.
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