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Alpha-Synuclein in Lewy Body Disease and Alzheimer's Brain Pathology 9: 707-720(1999) SYMPOSIUM: Tau and Synuclein in Neuropathology Alpha-synuclein in Lewy Body Disease and Alzheimer’s Disease Makoto Hashimoto1 and Eliezer Masliah1,2 pointed to ␣-synuclein, also known as the precursor of the non-A␤ component of plaques (NACP), as a major Departments of 1Neurosciences and 2Pathology, University of California, San Diego, School of Medicine, La Jolla, California factor in the pathogenesis of AD and LBD (76). Alpha- 92093-0624 synuclein was first isolated by Maroteaux and co-work- ers by expression screening of a torpedo cDNA library Alzheimer’s disease (AD) and Lewy body disease using anti-serum against purified synaptic vesicles (72). (LBD) are the most common causes of dementia in the elderly population. Previous studies have shown The term synuclein was proposed because immunoreac- that cognitive alterations in these disorders are tivity was observed in presynaptic termini and nuclei, associated with synaptic loss. Injury and loss of although nuclear immunoreactivity has not been noted synapses might be associated with altered function in subsequent studies. Nakajo and co-workers purified a of synaptic proteins. Among them, recent studies presynaptic phosphoprotein (PNP14) from bovine brain have shown that abnormal aggregation and accumu- that was very similar to synuclein (86, 122), which is ␣ lation of synaptic proteins, such as -synuclein, now known as ␤-synuclein. might be associated with plaque formation in AD and In 1993 Saitoh and coworkers identified ␣-synuclein Lewy body formation in LBD. Further reinforcing the as NACP, which was a non-amyloid protein that co-puri- hypothesis that ␣-synuclein plays a major role in the pathogenesis of these disorders, recent work has fied with amyloid from AD brains (125). NACP is the shown that mutations that alter the conformation of human homologue to murine ␣-synuclein (17). Jakes this molecule are associated with familial forms of and Goedert purified both ␣-synuclein and ␤-synuclein Parkinson’s disease. The mechanisms by which from human brain using monoclonal antibodies raised altered function or aggregation of ␣-synuclein might against tau protein (48). At the same time, Clayton and lead to neurodegeneration are not completely clear; coworkers identified synelfin, the avian homologue of however, new evidence points to a potential role for ␣-synuclein, whose expression was dramatically down- this molecule in synaptic damage and neurotoxicity regulated during a critical period for song learning in the via amyloid-like fibril formation and mitochondrial canary (28), suggesting that synelfin might play a criti- dysfunction. In this manuscript we review the data linking ␣-synuclein to the pathogenesis of AD and cal role in neural plasticity. ␥ LBD. More recently, -synuclein was isolated as a synucle- in-like molecule expressed predominantly in peripheral Introduction sympathetic neurons (2). Gamma-synuclein was cloned Alzheimer’s disease (AD) and Lewy body disease from an EST library and identified as the breast cancer (LBD) are the most common causes of dementia in the specific gene (BCSG1) whose expression was previous- elderly population. Previous studies have shown that ly observed in invasive types of breast cancer (52). In cognitive alterations in these disorders correlate with 1997 Polymeropoulos and colleagues identified a mis- synaptic loss (20, 121). It is postulated that synaptic loss sense mutation (A53T) in ␣-synuclein in Italian and and injury might be associated with altered function of Greek families with autosomal dominant Parkinson’s synaptic proteins (75). Among them, recent studies have disease (PD) (99). Shortly thereafter, Kruger and col- leagues identified another missense mutation (A30P) in ␣-synuclein in a German family (59). Following these Corresponding author: Dr. E. Masliah, Department of Neurosciences, University of seminal observations, neuropathologic and biochemical California, San Diego, La Jolla, CA 92093-0624; Tel.: (858) 534- studies established that abnormal aggregates of ␣-synu- 8992; Fax (858) 534-6232; E-mail: emasliah @ucsd.edu Alpha-synuclein belongs to a family of proteins that includes ␤-synuclein and ␥-synuclein (14) (Figure 1). Beta-synuclein is encoded by a gene in chromosome 5 and ␥-synuclein by a gene on chromosome 10 (Table 1). Both ␣-synuclein and ␤-synuclein are abundantly expressed in the central nervous system (CNS) (48), whereas ␥-synuclein is expressed mainly in the periph- eral nervous system (2). Although N-terminal regions of the synucleins are highly similar, C-terminal regions are divergent except for the last 10 amino acids, which are conserved between ␣-synuclein and ␤-synuclein (48). Alpha-synuclein shows more homology with ␤-synucle- in than with ␥-synuclein. Although the Ser118 residue of ␤ Figure 1. Synuclein proteins: Structure and relationship to neu- -synuclein was previously characterized as a potential rodegenerative disorders. phosphorylation site of calmodulin kinase (87), this ser- ine residue is not conserved in ␣-synuclein and ␤-synu- clein. No studies have been published on the phospho- rylation state of a-synuclein. Interestingly, ␤-synuclein has a deletion of part of the NAC domain, which makes it non-amyloidogenic. The structural relationship between ␣-synuclein and ␤-synuclein is similar to that between amyloid precursor protein (APP) and its relat- ed protein, APLP2 (130). APP is one of several related proteins that belong to the APP superfamily (109). Among them, APLP2 is highly homologous with APP ␤ Figure 2. The synuclein family of proteins. except for absence of the amyloidogenic A domain. The biological significance for the evolution of related Synuclein Chromosome MW (kDa) Disease molecules with amyloidogenic and non-amyloidogenic (approx) domains remains a matter for future study. alpha $q21.3-q22 19 Lewy body disease Several mRNAs are known to arise from alternative splicing of the ␣-synuclein gene. In rats, two alternative beta 5q35 14 - transcripts have been reported (73). These include gamma 10q23 12 Breast cancer SYN2, which has a distinct C-terminal region, and SYN3, which is truncated at the N-terminal region Table 1. Gene localization of alpha, beta and gamma synucle- ␣ ␣ in. (Figure 2). In humans, -synuclein 126 and -synucle- in 112 have been identified (12, 126), which result in clein were major components of Lewy bodies (LBs) and deletions from codon 41 to 54 and from 103 to 130, dystrophic neurites in LBD (119). respectively. These alternatively spliced products are far less abundant than ␣-synuclein and their biological sig- The synuclein family of proteins nificance is unknown (Figure 2). Alpha-synuclein is a 140 amino acid protein with lit- tle or no secondary structure (131) encoded by a gene Alpha-synuclein physiology located on chromosome 4. Sequence analysis suggests Although ␣-synuclein is regarded as a presynaptic that it has three major domains: 1) an N terminal region protein with a potential role in neuronal plasticity (28), composed of incompletely an repeated KTKEGV little is known of its actual normal function. motifs, 2) a NAC domain that is extremely hydrophobic, Immunohistochemical analyses using laser scanning and 3) a C-terminal region with a negative charge (14) confocal microscope showed that ␣-synuclein (Figure 1). Interestingly, both the A53T and A30P muta- immunoreactivity was predominantly located in presy- tions lie in the N-terminal region, suggesting that the N- naptic regions (Figure 3). Immunoelectron microscopic terminal domain may be critical for LB formation studies demonstrated loose association with synaptic (Figure 1). vesicles, suggesting that ␣-synuclein might play a role 708 M. Hashimoto and E. Masliah: ␣-synuclein in LBD and AD Figure 3. Alpha-synuclein immunoreactivity in AD and LBD. A) ␣-synuclein colocalization to synapses in normal control; B,C) ␣-synu- clein colocalization with ubiquitin and synaptophysin in LBD; D,E) NAC immunoreactivity in a plaque in AD; F,G) congo red and ultra- structure of ␣-synuclein aggregates in vitro; H) C-term ␣-synuclein immunoreactive LB; I,J) N-term ␣-synuclein immunoreactive LB; K,L) C-term ␣-synuclein immunoreactive neurites; M) C-term ␣-synuclein immunoreactive LB in substantia nigra; O) double labeling for ␣-synuclein and cyt-C; P) LB-like inclusions in tg mice. in function of synaptic vesicles (45). Similarly, ultra- possibility that another function of the synucleins may structural analysis of ␣-synuclein in platelets showed its be in specific signal transduction pathways. In this con- association with secretory vesicles and plasma mem- text, it is noteworthy that expression of ␥-synuclein con- brane (39). More recently, ␣-synuclein has been shown ferred increased invasive properties to breast cancer to interact with a cellular vesicular system (50) (Dale cells (53) and also selectively degraded neurofilaments Bredeson, personal communication) indicating that it in primary cultured neurons (10), suggesting that synu- might play a critical role in the release or uptake of neu- cleins may influence the integrity of cytoskeleton net- rotransmitters. works. Finally, synphilin-1 has recently been identified In developmental studies of the murine brain, expres- using a yeast two-hybrid method as a cytosolic binding sion of ␣-synuclein was first detectable at embryonic protein for ␣-synuclein. Further characterization of this days 12 to 15, followed by a dramatic increase at later molecule may provide clues as to additional physiolog- time points (41).
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