Tau and Alpha-Synuclein
Tau and Alpha-Synuclein Dysfunction and Aberrant Aggregates Define Distinct Neurodegenerative Diseases
The past two years have been extremely prolific in the area of neurodegenerative research, particularly with regard to diseases involving the proteins tau and synuclein. Tau aggregation in the form of filaments has long been implicated in diseases such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), as well as others. The recent discovery of tau gene mutations in patients afflicted by a heterogeneous disease entity termed frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) has provided genetic corroboration for the importance of tau in disease and opens novel avenues of investigation into the nature of tau dysfunctions that lead to the demise of neurons. The discovery of mutations in α-synuclein in familial cases of Parkinson’s disease (PD) has led to the revelation that this protein likely plays a prominent role in the etiology of several sporadic neurodegenerative disorders including PD, dementia with Lewy body (DLB) and multiple system atrophy (MSA), collectively grouped as synucleinopathies. In common with the subset of neurodegenerative diseases known as tauopathies because they are characterized by prominent filamentous tau aggregates in neurons and glia, similar fibrillary inclusions also accumulate in the brains of patients with synucleinopathies, but these inclusions are comprised predominantly of α-synuclein aggregates. In this chapter, the current knowledge of synuclein and tau proteins and their possible aberrant, malevolent role(s) in the onset and/or progression of brain diseases is reviewed.
Figure 1. Amino acid sequence alignment of the human synuclein proteins. The imperfect repeats of the type KTKEGV are identified. The black background highlights amino acid residues conserved between all four proteins. The sequences of α- and β-synucleins were obtained from Jakes et al (15), and γ-synuclein and synoretin were obtained from Ji et al (26) and Surguchov et al (8), respectively.
Synucleins are small proteins (123-143 amino acids) characterized by repetitive imperfect repeats (KTKEGV) distributed throughout most of the amino-terminal half of the polypeptide and an acidic carboxyl-terminal region (see Figure 1). The first synuclein was cloned from the electric ray, Torpedo california, by screening an expression library with an antiserum raised against cholinergic vesicles (1). This protein was named synuclein due to its initial localization within the neuronal nuclei and presynaptic nerve terminals; however, localization of mammalian synucleins to the nucleus was not confirmed by subsequent studies. Three human synuclein proteins, termed α, β, and γ, are encoded by separate genes mapped to chromosomes 4q21.3-q22 (2-4), 5q23 (4,5) and 10q23.2-q23.3 (6,7), respectively. The most recently cloned synuclein protein, synoretin, has a close homology to γ-synuclein and is predominantly expressed within the retina (8).
α-synuclein, also referred to as the non-amyloid component of senile plaques precursor protein (NACP) (9), SYN1 (10) or synelfin (11), is a heat-stable, "natively unfolded" protein (12,13) of poorly defined function. It is predominantly expressed in central nervous system (CNS) neurons where it is localized to presynaptic terminals (11,14-16). Although highly over-exposed Northern blots suggest that α-synuclein also may be expressed at low levels in many peripheral organs, these data must be interpreted with caution (9). Expression of α-synuclein has also been demonstrated in a megakaryocyte cell line and in platelets, where it is loosely associated with organelles such as the endoplasmic reticulum (17). Electron microscopy studies have localized α-synuclein in close proximity to synaptic vesicles at axonal termini (11,16), suggesting a role for α-synuclein in neurotransmission or synaptic organization, and biochemical analysis has revealed that a small fraction of α-synuclein may be associated with vesicular membranes but most α-synuclein is cytosolic (11,18). Further supporting the notion that it may have a vesicular function, a-synuclein can bind to rat brain vesicles in vitro (19). Structurally, α-synuclein is predicted to form amphipathic helixes that can associate with phospholipid bilayers (11), and an increase in α-helical secondary structure correlates with the binding of α-synuclein to small synthetic acidic unilamellar vesicles (13). The expression pattern of α-synuclein is altered in subsets of neurons that form the brain nuclei involved in male zebra finch song learning during the critical developmental period when singing is acquired (11). This suggests that α-synuclein may be involved in neuronal plasticity, although it does not seem to play a role in initial synaptic formation since it localizes to synapses after they are formed in cultured rat hippocampal neurons (14). Interestingly, α- and β-synucleins are selective inhibitors of mammalian phospholipase D2 and hence may play a role in the control of synaptic vesicle cycling (20).
The second member of the synuclein family that was identified is known as β-synuclein, initially named phosphoneuroprotein-14 or PNP-14, and it is a heat-stable protein predominantly expressed in neuronal axon termini of CNS neurons (15,21-23), although it has also been localized to testicular Sertoli cells (24). Although it is the least studied synuclein, it is highly homologous at the amino acid sequence level to a-synuclein and the localization of both proteins overlaps extensively in neurons, suggesting that the functions of α- and β-synuclein may be similar.
The third protein discovered to be homologous to α-synuclein is γ-synuclein (also termed persyn or breast specific cancer gene-1; BSCG-1) (25,26) and it also is expressed in brain and as well as in spinal cord, but it is most abundant in the peripheral nervous system (PNS) including neurons of the dorsal root ganglia and trigeminal ganglia (7,25)(see clone D3 in ref. 27). In addition, γ-synuclein is highly expressed in the stratum granulosum of the epidermis (28) and at low levels in several other organs (7,26). Unlike α- and β-synucleins, γ-synuclein is distributed throughout the neuronal cytosol, (25) where it may alter the metabolism of the neuronal cytoskeleton (29). Interestingly, γ-synuclein expression is upregulated in advanced infiltrating breast carcinoma (6,26), and overexpression in breast cancer cells augments cell motility, invasiveness and metastasis (30). Furthermore, synuclein proteins may be involved in signaling, as the expression of synoretin affects the regulation of signal transduction pathways by activating Elk-1 (8).
Alpha-synuclein was first associated with a neurodegenerative disease when a fragment thereof corresponding to amino acids 61-95, referred to as the non-amyloid component of senile plaques (NAC), was isolated from proteolytically digested sodium dodecyl sulfate-insoluble fractions of Alzheimer’s brain (9). In addition, antibodies to NAC recognize a significant percentage of diffuse and mature plaques (9,31-33). Although NAC may extend beyond amino acids 61-95 (9), the full length protein is not a component of plaques since plaques are not labeled by antibodies recognizing either ends of α-synuclein. NAC may be involved in the formation of amyloid senile plaques, as it can form amyloidogenic aggregates (32) and can stimulate the aggregation of b amyloid, the major component of plaques (34). These findings notwithstanding, the role of NAC in AD pathogenesis still remains to be evaluated. Interestingly, one study has suggested that a dinucleotide repeat polymorphism in the promoter of α-synuclein may confer protection against the apolipoprotein E e4 allele associated with AD (35), however this finding was not confirmed in a later study (36).
Genetic and histopathological findings have illuminated the significant contribution of α-synuclein to the etiology of PD. The identification of point mutations in α-synuclein in a small number of familial cases of PD strongly supports the notion that synuclein may play a causal role in this disease. Autosomal dominant mutations in α-synuclein were identified in a German kindred harboring an A30P mutation due a G to C transversion at position 88 (37) and in a large Italian family (the Contorsi kindred) and five Greek families with a A53T mutation resulting from an G to A transition at position 209 (38,39). Families harboring the A53T mutation may have existed in close contact suggesting a possible common ancestor (40). Thus far α-synuclein mutations resulting in disease have only been found in a small number of kindreds afflicted with familial PD. Analysis of large number of patients with sporadic or familial cases of either PD or DLB, as well as a small number of patients with MSA, failed to reveal mutations in α-synuclein (41-50). Furthermore, no mutations in the γ-synuclein gene have been demonstrated in families with PD (51).
Mounting evidence supports the idea that a-synuclein is the major component of several proteinaceous inclusions characteristic of specific neurodegenerative diseases. Pathological synuclein aggregations are restricted to the α-synuclein isoforms as β and γ-synucleins have not been detected in these inclusions. The presence of α-synuclein positive aggregates is disease-specific. Lewy bodies, neuronal fibrous cytoplasmic inclusions that are histopathological hallmarks of PD and DLB (52,53) are strongly labeled with antibodies to α-synuclein (54-61). Dystrophic ubiquitin-positive neurites associated with PD pathology, termed Lewy neurites (LN) (62), and CA2/CA3 ubiquitin neurites are also a-synuclein positive (54,56,58-60). Furthermore, pale bodies, putative precursors of LBs, (58,60,61), thread-like structures in the perikarya of slightly swollen neurons (61) and glial silver positive inclusions in the midbrains of patients with LB diseases (63) are also immunoreactive for α-synuclein. α-synuclein is likely the major component of glial cell inclusions (GCIs) and neuronal cytoplasmic inclusions in MSA and Hallervorden-Spatz disease (brain iron accumulation type 1) (60,64-68). α-synuclein immunoreactivity is present in some dystrophic neurites in senile plaques in AD (33), but is not detected in Pick bodies, neurofibrillary tangles (NFTs), neuropil threads, or in neuronal or glial inclusion characteristic of PSP, CBD, motor neuron disease and trinucleotide-repeat diseases (59,60).
Further evidence supports the notion that α-synuclein is the actual building block of the fibrillary components of LBs, LNs and GCIs. Immunoelectron microscopic studies have demonstrated that these fibrils are intensely labeled with α-synuclein antibodies in situ (31,57,60,61,65,68). Sarcosyl-insoluble α-synuclein filaments with straight and twisted morphologies can also be observed in extracts of DLB and MSA brains (54,67). Moreover, α-synuclein can assemble in vitro into elongated homopolymers with similar widths as sarcosyl-insoluble fibrils or filaments visualized in situ (69-73). Polymerization is associated with a concomitant change in secondary structure from random coil to anti-parallel β-sheet structure (73) consistent with the Thioflavine-S reactivity of these filaments (72,73). Furthermore, the PD-associated α-synuclein mutation, A53T, may accelerate this process, as recombinant A53T α-synuclein has a greater propensity to polymerize than wild-type α-synuclein (69,71,73). This mutation also affects the ultrastructure of the polymers; the filaments are slightly wider and are more twisted in appearance, as if assembled from two protofilaments (69-71). The A30P mutation may also modestly increase the propensity of a-synuclein to polymerize (73), but the pathological effects of this mutation also may be related to its reduced binding to vesicles (19). Interestingly, carboxyl-terminally truncated α-synuclein may be more prone to form filaments than the full-length protein (74). Although the pathological implications of the latter finding is still unclear, it is possible that aberrant proteolysis of α-synuclein may form "seeds" that could initiate α-synuclein filament assembly.
Figure 2. Schematic of exon organization and the six brain tau isoforms generated by alternative splicing. Alternative splicing of exons 2, 3 and 10 produce the six alternative products. Putative exons 6 and 8 are not used in brain. Exon 4A, which is also not used in the brain, is included in the PNS leading to the translation of larger tau isoforms, termed "big tau" (see text). Black bars depict the 18 amino acid MT binding repeats.
Tau is a collection of microtubule (MT) associated proteins (MAPs) (75) expressed from a single gene on chromosome 17 (76,77). In the adult human brain, 6 isoforms ranging between 352 and 441 amino acids in length are produced as a result of alternative RNA splicing (78,79) (Figure 2). The incorporation or exclusion of exon 2 or exons 2 and 3 results in proteins with 0 (0N), 29 (1N) or 58 (2N) amino acid inserts in the amino-terminal region. Similarly, exon 10 can be alternatively spliced to yield products containing either three (3R) or four (4R) tandem repeats of 31 or 32 amino acids. In adult brain, 3R and 4R tau are present at approximately equal amounts and 2N tau isoforms are significantly underrepresented relative to 0N or 1N isoforms (80,81). The expression of tau isoforms is developmentally regulated, as only the smallest tau polypeptide (0N, 3R) is expressed in fetal brain (78,80). Furthermore, alternative splicing and inclusion of exon 4A (77,82) yields a group of higher molecular weight tau proteins, termed "big tau", which is expressed predominantly in the peripheral nervous system (82-84). Tau is preferentially found in neurons (85,86) but can also be detected in some oligodendrocytes and astrocytes (86-89).
The ability of tau to induce MT assembly, nucleation and bundling is well documented (75,90-96). The MT binding domain of tau resides within the carboxyl-terminal region containing the three or four MT-binding repeats (3R, 4R) and 13 or 14 amino acid inter-repeats (97-99). Individual repeats are capable of binding MTs, albeit with weaker affinities than the full-length protein (100). Although each repeat makes a significant contribution to the overall MT affinity (101), MT binding is more complex than a simple linear array of binding sites (94,95). The spacer between repeats MT-binding repeats one and two (R1-R2) can also contribute to MT binding as it has more than twice the binding affinity than any individual repeat (101). Furthermore, a proline-rich region upstream of the repeat region (94), more precisely the sequence KKVAVVR (amino acids 215-221), exerts a strong positive influence on MT binding and assembly (102). The molecular details governing the tau-MT interaction remains incompletely defined and controversial, nevertheless it appears that tau can bind to at least two regions in either a and b tubulin [(103), and references herein]. Four-repeat tau has a greater MT polymerization and binding capacity than 3R-tau (80,98). The amino-terminal inserts do not significantly contribute to the binding affinity of tau; however, they may induce MT bundling (94). The ability of tau to bind and modulate MT assembly is negatively regulated by phosphorylation (90,93,104-106).
Surprisingly, tau is not essential for MT function since disruption of expression by a genetically engineered null mutation does not result in an overt phenotype (107). Moreover, depletion of axonal tau in rat sympathetic neurons by microinjection of anti-tau antibodies had no detectable effects on the dynamics of axonal MTs (108). Thus, it seems likely that the ability of tau to modulate MT assembly can be compensated for by other MAPs.
The distribution of tau in cultured rat sympathetic and hippocampal neurons suggests that it may serve functions other than the stabilization of MTs. In these cultures, tau is more concentrated at the distal end than the proximal end of axons even though axonal MTs in the distal end are less stable and turn over more rapidly (109,110). It is possible that these apparent discrepancies may be the result of differential phosphorylation of tau within these axonal regions, but these observations also suggest that the abundance of tau at the growth cone neck may reflect an alternative role for tau. Tau expression can inhibit kinesin-dependent trafficking of organelles such as mitochondria and vesicles (111). Additionally, the amino-terminal projection domain of tau interacts with the plasma membrane, although the importance of this observation is still unknown (112). Furthermore, tau has been shown to exist in complex with phospholipase C-g (113) and to increase the activity of this enzyme (114).
In AD, tau aggregates into cytoplasmic inclusions in the form of neurofibrillary tangles (NFTs) in neuronal cell bodies, and neuropil threads and dystrophic neurites of senile plaques in neuronal processes (115). Ultrastructurally, these aberrant structures are comprised of 8-20nm twisted double-helical ribbons, referred to as paired helical filaments (PHFs), (116,117) and the less abundant 15 nm wide straight filaments (SFs) (118,119). Compelling biochemical and immuno-electron microscopic studies have demonstrated that PHFs are comprised of tau (120-124). SFs are a structural variant of PHFs and are likely entirely composed of tau (118). Abnormally aggregated tau isolated from AD brain, referred to as PHF-tau (or A68), contains all six CNS tau isoforms (125) aberrantly hyperphosphorylated at >25 Ser or Thr residues (126-128). It is still unclear which enzymes are responsible for this hyperphosphorylation of tau, as numerous kinases and phosphatases can modulate tau phosphorylation in vivo and/or in vitro (129,130). It is likely that a change in a combination of enzymatic activities is involved in generating hyperphosphorylated PHF-tau.
The mechanism of PHF-tau formation in neurons remains enigmatic. Since hyperphosphorylation is the most prominent difference between PHF-tau and normal tau, it would be reasonable to hypothesize that phosphorylation may induce tau filament formation. However, there is no direct evidence to support this model, and non-phosphorylated, recombinant tau can assemble into filaments in vitro (131). It is more likely that abnormal phosphorylation increases the pool of MT-unbound tau which then becomes available for PHF formation. Supporting this notion are the findings that: 1) hyperphosphorylation of tau precedes PHF formation (132,133), 2) phosphorylation inhibits MT binding (90, 93, 106,134), and 3) the ability of PHF-tau to bind to MTs is greatly impaired, but this loss of function can be overcome by dephosphorylation (93,105,135).
Interestingly, tau filament assembly in vitro can be facilitated by long polyanionic molecules such as strongly or moderately sulfated glycosaminoglycans and nucleic acids (136-140). Moreover, sulfated glycosaminoglycans and nucleic acids has been shown to prevent tau MT-binding, and heparin sulfate, chondroitin sulfate and dermatan sulfate proteoglycans have been co-localized with NFTs of AD brains (136,141,142). It is unclear how sulfated glycosaminoglycans appear within the cytoplasm, although a likely explanation would involve leakage from membrane-bound organelles.
PHF-tau also is modified by ubiquitination (143), glycation (144,145), and N-linked glycosylation (146). Ubiquitination occurs after aggregation, probably as an attempt by the cellular machinery to degrade these protein aggregates, and it is unlikely to contribute to PHF formation (133,147). Glycation is a non-enzymatic addition of reduced carbohydrates, and the presence of this modification is likely to result from the slow turnover of PHFs. The importance of N-linked gycosylation is undetermined, although it may contribute to the maintenance of PHF structure (146).
FTDP-17 refers to a group of autosomal dominant hereditary neurodegenerative disorders characterized by behavioral changes with subsequent cognitive disturbance and, in some cases, parkinsonism (148). Most, if not all, FTDP-17 families show tau deposits either in neurons or in both neurons and glia without accompanying amyloid deposition (149-157). Genetic analysis has revealed 12 different mutations in the tau gene in at least 26 FTDP-17 families, establishing that in FTDP-17 kindreds tau mutations are pathogenic for the disease. The mutations can be divided into two functional groups: missense mutations that impair the ability of tau to bind to MTs and promote MT assembly, and exonic or intronic mutations that alter the inclusion of exon 10 during splicing. Missense mutations G272V, D280, P301L, V337M and R406W belong to the former category (81,155,158,159). These mutations may lead to pathogenesis through an initial loss of function, followed by a gain of toxic effect. The reduced capacity of these mutants to stabilize MTs may lead to a loss of MT function, such as fast axonal transport. Pathology may subsequently be compounded by a progressive accumulation of tau in the cytoplasm and eventual aggregation into insoluble filaments. Moreover, mutations P301L, V337M, and R406W may accelerate tau filament formation (160,161). Consistent with the location of these mutations within tau, aggregated tau from cases with mutation V337M or R406W is predominantly comprised of all six CNS tau isoforms, while only 4R-tau is present in the case of P301L (81,162).
Figure 3. Structure of the putative inhibitory RNA stem loop structure at the 5’ boundary of the intron following exon 10. Pathogenic mutations that can affect the stability of this secondary structure are depicted.
Some pathogenic missense mutations and silent mutations at or close to exon 10 can alter the splicing efficiency of this exon, as demonstrated by exon trapping analysis (155,163,164). The mutations may affect splicing via three different mechanisms. First, In the in cases of the known intronic mutations and the missense mutation S305N, it has been proposed that altered splicing efficiency may be due to the disruption of a putative inhibitory RNA stem loop structure at the 5’ boundary of the intron following exon 10 (Figure 3) (155,163). This secondary structure may compete with the U1 snRNP or other splicing factors for the binding of the splice donor site, and its destabilization leads to the increased inclusion of exon 10. However, attempts to rescue the putative function of the stem-loop structure with compensatory double mutants were not successful, suggesting that other elements beside the secondary structure are involved (155). The S305N mutation also changes the 5’splice site of intron 10 to a stronger splice site (GUguga to AUguga) (165), which likely also contributes to the effect on splicing by this mutation. Consistent with this pathogenic mechanism, an increased ratio of exon 10+/exon 10-tau RNA in the brains of patients with intronic mutations has been reported (163). A second mechanism by which splicing is affected is demonstrated by the N279K mutation which may enhance the insertion of exon 10 by improving an exon-splicing enhancer. At the RNA level, this mutation changes a nucleotide stretch from TAAGAA to GAAGAA. The latter sequence is a repeat of GARs (where R is a purine) which can act as an exon-splice enhancer (166-169). The finding that the deletion of nucleotides AAG associated with the D280 mutation obliterates exon 10 inclusion strongly supports The notion that this nucleotide stretch is a splicing enhancer is supported by the finding that the deletion of nucleotides AAG by the D280 mutation obliterates exon 10 inclusion (155). The Finally, a third mechanism is demonstrated by the silent mutation L284L (CTT® CTC) which likely affects splicing because it disrupts the sequence UUAG that can act as a putative exon splicing silencer (170), and thereby increasing increases the ratio of 4R-/3R-tau exon 10+/exon 10-tau (155) These three different modes of affecting splicing exon 10 are supported by exons trapping experiments (REF) and in some cases by the reported increased ratio of exon 10+/exon 10-tau messenger RNA in the brains of patients with intronic mutations (REF). Consistent with the notion that an alteration in RNA splicing is the cause of pathogenesis, biochemical postmortem analysis of the brains of affected patients with mutations predicted to increase exon 10 splicing (ie., E10+14, N279K, E10+3 mutations) showed an increase in the abundance of 4R-tau over 3R-tau and the specific accumulation of aggregated 4R-tau (81,150,154,162,171).
The mechanism by which changes in the 3R/4R-tau ratio lead to neuronal and, in some cases, glial dysfunction and death is still nebulous. Four repeat-tau and 3R-tau may bind to distinct sites on MTs (101), and the over-production of one group of isoforms may result in a pool of MT-unbound tau that may polymerize into filaments over time. It is also possible that a specific ratio of tau isoforms is required for the normal maintenance and function of MTs. Although speculative, the possibility that specific isoforms might have other, undetermined functions should not be overlooked.
Pick’s disease is a frontotemporal-type dementia characterized by the presence of Pick bodies, round-shaped neuronal inclusions composed of granular material together with 10-20 nm diameter filaments (172). These disease specific filamentous tau inclusions contain 3R-tau isoforms exclusively (173,174). The reasons for this selective aggregation of isoforms is unknown, but a possible explanation is that neurons expressing specifically these forms of tau are more vulnerable in Pick’s disease. The restricted expression of 3R-tau in the granule cell layer of the dentate gyrus demonstrates that expression of tau isoforms can be cell-type specific (79). This concept has not been extensively studied and further evaluation is certainly warranted.
PSP and CBD are late onset neurodegenerative disorders characterized by both neuronal and glial tau inclusions. Aggregated tau in these diseases is predominantly comprised of 4R-tau isoforms (175). In CBD, tau precipitates in the form of astrocytic plaques, oligodendroglial "coil bodies", and neuronal inclusions sometimes termed corticobasal bodies (176,177). Neuronal tau in PSP brains aggregates in the form of classical flame-shaped NFTs or globose NFTs (176). PSP also features distinctive glial tau inclusions termed oligodendroglial "coiled-bodies", tufted astrocytes, and thorn-shaped astrocytes (177).
Genetic changes in the tau gene may contribute to the risk of developing PSP. Conrad et al (178) reported a link between PSP and a polymorphism dinucleotide repeat region found between exons 9 and 10 of the tau gene. Subsequent studies confirmed this correlation (179-181), and it was recently demonstrated that this association is due to a specific haplotype that also contains at least 8 single nucleotide polymorphisms (182).
Two major groups of neurodegenerative diseases, synucleopathies and tauopathies, exhibit aberrant proteinaceous inclusions which result in cellular dysfunction. There may be multiple mechanisms by which these aggregates mediate their destructive consequences. First, the accumulation of either synuclein or tau in inclusions may reduce the levels of functional molecules, which alone may be detrimental to the cell. However, the presence of inclusions may also act as a barrier that interferes with overall cellular functions such as axonal transport or cellular morphology. In the end, it is likely that both the depletion of functional protein and the presence of cytoplasmic obstacles are instrumental in the ultimate demise of neurons. Further investigation, including the development of transgenic mouse models, is warranted to enhance the current understanding of normal synuclein and tau functions as well as the mechanism(s) involved in the intracellular aggregation of these proteins in order to improve preventative and therapeutic strategies.
B. I. G. is a recipient of a fellowship from the Human Frontier Science Program Organization. C.A. W. is a Howard Hughes predoctoral fellow. This work was supported by grants from the National Institute on Aging, the Dana Foundation and a Pioneer Award from the Alzheimer’s Association. The authors want to thank Dr. S. Rueter for her critical reading of this manuscript. We also thank our colleagues in the Center for Neurodegenerative Disease Research, Departments of Pathology and Laboratory Medicine, Neurology, Psychiatry, and the Penn Alzheimer Center for their assistance; and the families of patients who made this research possible.
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