Frontotemporal Disease (FTD)*
*Also referred to as Frontotemporal Dementia.
FRONTOTEMPORAL DEMENTIA WITH PARKINSONISM LINKED TO CHROMOSOME 17 (FTDP-17): FAMILIAL TAUOPATHIES CAUSED BY TAU GENE MUTATIONS
Abundant neurofibrillary tangles (NFTs) composed predominantly of aggregated paired helical filaments (PHFs) formed by abnormally phosphorylated tau proteins known as PHFtau are one of the 2 signature brain lesions required for a definite diagnosis of Alzheimer's disease (AD), but several other hereditary and sporadic neurodegenerative disorders are characterized by abundant accumulations of filamentous tau inclusions in specific populations of neurons with or without similar glial cell inclusions. Despite phenotypic and genotypic heterogeneity, central nervous system (CNS) diseases with prominent tau-rich filamentous inclusions are collectively known as tauopathies. While some tauopathies (e.g. AD) are associated with other diagnostic lesions (e.g. amyloid plaques), the accumulation of filamentous tau inclusions is the predominant or only diagnostic neuropathological feature of several neurodegenerative tauopathies, although these inclusions are accompanied by neuron loss and gliosis. Here we review evidence based on the discovery of pathogenic tau gene mutations in fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) and a growing body of other data indicating that the progressive accumulation of intracellular filamentous tau inclusions alone is sufficient to induce the onset and/or progression of neurodegenerative disease due to the dysfunction and death of affected neurons and glial cells in selectively vulnerable regions of the CNS.
Neurofibrillary lesions are intracellular aggregates of abnormal filaments, and much of the information on the pathobiology of these lesions comes from extensive studies of NFTs in AD which are formed primarily by PHFs although some straight filaments (SFs) also are seen in these lesions (Kidd, 1963). PHFs consist of two ribbon-like strands twisting around one another in a helix with a periodicity of 80 nm and a width of 8-20 nm (Crowther and Wischik, 1985). SFs appear to be structural variants of PHFs (Crowther, 1991) since a PHF may undergo a transition to a SF, and both are formed by two C-shaped units that differ in their arrangement within the filament (Crowther, 1991). Moreover, PHFs and SFs are formed exclusively by aberrantly hyperphosphorylated tau proteins referred to as PHFtau (Goedert et al., 1988; Kondo et al., 1988; Wischik et al., 1988; Kosik et al., 1988; Lee et al., 1991; Crowther, 1991).
Filaments resembling PHFs and SFs have been assembled in vitro from recombinant tau fragments or full-length tau (Crowther et al., 1992; Wille et al., 1992; Crowther et al., 1994), and this assembly process is facilitated by negatively charged molecules, such as sulfated glycosaminoglycans and nucleic acids (Goedert et al., 1996; Kampers et al., 1996; Perez et al., 1996; Arrasate et al., 1997). Highly sulfated molecules have a more potent effect (Hasegawa et al., 1997), and heparin prevents tau from binding to microtubules (MTs), promotes MT disassembly (Goedert et al., 1996; Hasegawa et al., 1997), and stimulates tau phosphorylation by several kinases (Mawal-Dewan et al., 1992; Brandt et al., 1994; Yang et al., 1994; Hasegawa et al., 1996; Goedert et al., 1997a; Hasegawa et al., 1997). Since heparan sulfate, chondroitin sulfate and dermatan sulfate proteoglycans are present in AD NFTs (Snow et al., 1992; DeWitt et al., 1993; Goedert et al., 1996), sulfated glycosaminoglycans may interact with tau and promote the formation of filamentous tau lesions.
Tau is an abundant microtubule-associated protein (MAP) localized predominantly to axons in CNS and peripheral nervous system (PNS) neurons (Binder et al., 1985; Couchie et al., 1992), but it also is detected in low abundance in CNS astrocytes and oligodendrocytes (Shin et al., 1991; LoPresti et al., 1995) which may account for the presence of filamentous tau inclusions in glial cells in some tauopathies (Iwatsubo et al., 1994). In the normal adult human brain, six tau isoforms ranging from 352-441 amino acids are expressed by alternative splicing of a single tau gene on chromosome 17 (Goedert et al., 1988; Goedert et al., 1989a; Goedert et al., 1989b; Andreadis et al., 1992). Each isoform contains either three (3R-tau) or four (4R-tau) consecutive imperfect repeat motifs of 31 or 32 amino acids in the carboxy-terminal half of the protein (Goedert et al., 1989a; Goedert et al., 1989b) and 3R-tau and 4R-tau isoforms differ with respect to the presence or absence of 29 or 58 amino acids long amino-terminal inserts. The functions of the amino-terminal inserts are unknown, but the repeat motifs are MT-binding domains (Goedert and Jakes, 1990; Butner and Kirschner, 1991; Goode and Feinstein, 1994). Another large insert is present in the amino-terminal of an additional tau isoform ("big tau") expressed in the PNS (Couchie et al., 1992; Goedert et al., 1992b). The expression of alternatively spliced tau isoforms is developmentally regulated in the CNS, and only the shortest isoform ("fetal tau") is expressed in the immature human brain, but all six brain tau isoforms are expressed in the adult human CNS (Goedert et al., 1989a). Analysis of biopsy-derived normal human cortex showed that >50% of total tau has one amino-terminal insert, ~40% has no amino-terminal insert and only about 10% has both of these inserts, but the 4R-tau to 3R-tau ratio is held constant at ~1 (Hong et al., 1998).
Several functions of tau have been identified. For example, tau has been shown to promote tubulin polymerization into MTs (Weingarten et al., 1975), as well as to bind to and stabilize MTs (Drechsel et al., 1992). The MT-binding domains are separated by flexible inter-repeat sequences (Butner and Kirschner, 1991) that also contribute to optimal MT-binding by tau (Goode and Feinstein, 1994). The MT-stabilizing function of tau has been demonstrated in a number of studies using cell culture systems (Kanai et al., 1989; Knops et al., 1991; Kanai et al., 1992; Lee and Rook, 1992; Gallo et al., 1992; Bramblett et al., 1993; Lo et al., 1993), and tau may play a role in neurite extension (Knops et al., 1991), although tau "knock-out" mice show no adverse effects, and cultured cerebellar neurons from these animals have a normal complement of axons and dendrites (Harada et al., 1994).
Tau is phosphorylated primarily at a number of serine and threonine residues (Butler and Shelanski, 1986) and tau phosphorylation negatively regulates MT-binding (Drechsel et al., 1992; Biernat et al., 1993; Bramblett et al., 1993; Yoshida and Ihara, 1993). Indeed, PHFtau is hyperphosphorylated and unable to bind to MTs, but dephosphorylation restores the ability of PHFtau to bind MTs (Drewes et al., 1992; Bramblett et al., 1993; Yoshida and Ihara, 1993). Although phosphorylation ol serine 262 was suggested to be critical for impairing MT-binding (Biernat et al., 1993), it is likely that phosphorylation at multiple residues impairs MT-binding in PHFtau (Seubert et al., 1995).
AD PHFs are formed by PHFtau proteins that migrate as three major bands of approximately 68, 64, and 60 kDa (Greenberg and Davies, 1990; Lee et al., 1991), and dephosphorylation of PHFtau reveals the presence of all 6 brain tau isoforms (Lee et al., 1991; Greenberg et al., 1992; Goedert et al., 1992a; Liu et al., 1993). Initial studies suggested that serine and threonine residues were abnormally phosphorylated in AD PHFtau, and that these sites were not tau phosphorylation sites in normal adult human brains ( Lee et al., 1991; Hasegawa et al., 1992; Morishima-Kawashima et al., 1995). Further studies showed that the phosphorylation state of human fetal tau and rat CNS tau partially recapitulated that of PHFtau (Kanemaru et al., 1992; Bramblett et al., 1993; Goedert et al., 1993; Yoshida and Ihara, 1993), but subsequent studies of biopsy-derived normal human brain showed that freshly isolated adult human CNS tau was phosphorylated at almost all the same sites as PHFtau, albeit far less extensively (Garver et al., 1994; Matsuo et al., 1994). Nevertheless, at least one phosphorylation-dependent anti-PHFtau monoclonal antibody, i.e. AT100 or AT10 distinguishes PHFtau from normal adult or fetal tau (Matsuo et al., 1994), and this antibody recognizes an epitope that includes phosphothreonine212 and phosphoserine214 (Hoffmann et al., 1997; Zheng-Fischhofer et al., 1998).
Tau phosphorylation is determined by an exquisite equilibrium between kinase and phosphatase activities, and an imbalance of these activities may hyperphosphorylate tau to generate PHFtau. Indeed, the rapid dephosphorylation of normal adult human tau and the contrasting preservation of hyperphosphorylated epitopes of PHFtau in postmortem brains suggests that phosphatase activities may be reduced in AD brains. It is also possible that PHFtau aggregated into NFTs remains hyperphosphorylated because it is inaccessible to phosphatases. Similarly, overactive kinase activities can also initiate hyperphosphorylation and aggregation of tau, or further modify aggregated tau and prevent degradation. Thus, an imbalance of neuronal kinase/phosphatase activities may be one pathogenic mechanism whereby PHFtau forms filamentous inclusions that lead to the dysfunction and degeneration of affected cells in AD and related tauopathies. Although extensive efforts have been made to identify phosphatases involved in the generation of PHFtau, these enzymes remain largely unknown (Goedert et al., 1992; Drewes et al., 1993; Harris et al., 1993; Sontag et al., 1995; Sontag et al., 1996; Merrick et al., 1996; Merrick et al., 1997). On the other hand, many kinases have been implicated in the formation of PHFtau including: mitogen-activated protein kinase (MAPK, also known as ERK) (Drewes et al., 1992; Goedert et al., 1992; Latimer et al., 1995), glycogen synthase kinase-3 (GSK-3) (Hanger et al., 1992; Mandelkow et al., 1992; Ishiguro et al., 1993; Lovestone et al., 1994; Sperber et al., 1995; Lovestone et al., 1996; Hong and Lee, 1997b), cyclin-dependent kinase 5 (cdk5) (Baumann et al., 1993; Kobayashi et al., 1993), cAMP-dependent protein kinase (PKA) (Litersky et al., 1996), Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) (Litersky et al., 1996), MAP/microtubule affinity-regulating kinase (MARK) (Drewes et al., 1997), in addition to stress-activated protein kinases (SAPK, i.e. SAPK1, SAPK2a, SAPK2b, SAPK3 and SAPK4 (Goedert et al., 1997a) as well as p38/reactivating kinase (RK) and c-Jun N-terminal kinase (Reynolds et al., 1997a; Reynolds et al., 1997b). Although it is unknown if any of these kinases play an authentic role in the pathogenesis of PHFtau in the AD brain, one of the more promising candidate PHFtau kinases is GSK-3, which phosphorylates tau in vitro in non-neuronal (Lovestone et al., 1994; Sperber et al., 1995; Lovestone et al., 1996) and neuronal (Hong and Lee, 1997b) cells. GSK-3 was so named because it phosphorylates and inactivates glycogen synthase thereby catalyzing insulin-mediated glycogen synthesis (Cohen et al., 1982; Woodgett, 1991). In addition, insulin induces a phosphorylation-dependent down-regulation of GSK-3 activity and is abundant in the brain (Woodgett, 1990), as are insulin, IGF-1, and their receptors (Sara et al., 1982; Haselbacher et al., 1985; Marks et al., 1991). Moreover, insulin and IGF-1 regulate tau phosphorylation by inhibiting GSK-3 via a signal transduction pathway involving phosphatidylinositol 3-kinase and protein kinase B (Hong and Lee, 1997b), and lithium reversibly inhibits GSK-3 (Hong et al., 1997a) and reduces tau phosphorylation (Hong et al., 1997a). However, if GSK-3 plays an authentic role in tau phosphorylation in vivo, it is unlikely to be the only kinase to do so because no single kinase recapitulates all of the phosphorylation sites in PHFtau, and it is most plausible that multiple kinases contribute to the hyperphosphorylation of tau in a site-specific, sequential or combinatory manner.
Despite these uncertainties, a growing body of data on the neurofibrillary lesions in AD suggest that the formation of PHFtau has deleterious effects on neurons during the progression of this disorder. For example, the accumulation of PHFtau in the AD cortex correlates with the abundance of NFTs and the diminished levels of normal MT-binding competent tau in the CNS (Bramblett et al., 1992; Bramblett et al., 1993), and since PHFtau is unable to bind to MTs (Bramblett et al., 1993; Yoshida and Ihara, 1993), the conversion of normal tau into PHFtau could lower the levels of MT-binding tau, destabilize MTs, disrupt axonal transport thereby leading to the "dying back" of axons (Lee et al., 1991; Bramblett et al., 1992; Bramblett et al., 1993; Trojanowski and Lee, 1994; Lee et al., 1994). As a consequences of these events, corticocortical connections would be disrupted leading to incremental impairments of synaptic transmission followed by the emergence of cognitive impairments in AD.
Filamentous tau pathology is a hallmark of neurodegenerative tauopoathies other than AD, and a better understanding of these lesions is emerging at a more rapid pace in recent years (see Table 1 and Goedert et al., 1997b for a recent review).
Table 1. Neurological Diseases With Prominent Filamentous Tau Pathology
For example, in patients with Down's syndrome (Giaccone et al., 1989; Flament et al., 1990), dementia pugilistica (Roberts et al., 1990), and inclusion body myositis (Mendell et al., 1991; Askanas et al., 1992; Askanas et al., 1994), fibrillary tau lesions coexist with abundant Ab deposits Abundant fibrillary tau lesions are also found in conjunction with prion protein amyloid deposits in some cases of Gerstmann-Sträussler-Scheinker disease (Ghetti et al., 1989; Tagliavini et al., 1993), Jakob-Creutzfeldt disease (Hsiao et al., 1992) and prion protein cerebral amyloid angiopathy (Ghetti et al., 1996). However, fibrillary tau pathology is the dominant diagnositic feature of a number of tauopathies including: argyrophilic grain dementia (Braak and Braak, 1987; Itagaki et al., 1989), ALS/PDC of Guam (Hirano et al., 1961; Hof et al., 1994; Umahara et al., 1994; Buee-Scherrer et al., 1995), Pick ?s disease (Perry et al., 1987; Murayama et al., 1990; Lieberman et al., 1998b), corticobasal degeneration (CBD) (Paulus and Selim, 1990; Ksiezak-Reding et al., 1994; Mori et al., 1994; Wakabayashi et al., 1994), progressive supranuclear palsy (PSP) (Bancher et al., 1987; Flament et al., 1991; Schmidt et al., 1996), multiple system atrophy (MSA) (Papp et al., 1989), Niemann-Pick disease type C (Auer et al., 1995; Love et al., 1995; Suzuki et al., 1995), diffuse neurofibrillary tangles with calcification (Kosaka, 1994), Hallervorden-Spatz disease (Eidelberg et al., 1987), subacute sclerosing panencephalitis (McQuaid et al., 1994), and FTDP-17 (Wilhelmsen et al., 1994; Foster et al., 1997). Morover, in MSA, PSP, CBD, and FTDP-17, tau-positive lesions are also found in astrocytes and oligodendrocytes (Papp and Lantos, 1992; Nishimura et al., 1992; Iwatsubo et al., 1994; Yamaoka et al., 1996; Wijker et al., 1996; Baker et al., 1997; Foster et al., 1997; Froelich et al., 1997; Murrell et al., 1997; Wilhelmsen, 1997; Heutink et al., 1997; Spillantini et al., 1998). Significantly, the absence of other neuropathological lesions such as amyloid plaques and Lewy bodies in these diseases strongly suggests that tau dysfunction is directly involved in neuronal degeneration regardless of the clinical phenotypes of their diseases. Furthermore, as described in further detail below, genetic studies of FTDP-17 now provide unequivocal evidence in support of this point.
In many tauopathies, the immunohistochemical findings correlate with the recovery of sarkosyl-insoluble tau protein bands detected by the same epitope-specific anti-tau antibodies used to recognize PHFtau in AD. In Down's syndrome, Gerstmann-Sträussler-Scheinker disease, ALS/PDC of Guam, Niemann-Pick disease type C, and some cases of FTDP-17, sarkosyl-insoluble PHFtau consists of the same three major 68, 64, and 60 kDa bands seen in AD (Flament et al., 1990; Tagliavini et al., 1993; Auer et al., 1995; Buee-Scherrer et al., 1995; Mawal-Dewan et al., 1996; Spillantini et al., 1996). By contrast, in Pick ?s disease, only the 64 and 60 kDa insoluble tau bands are observed (Buee et al., 1996; Lieberman et al., 1998b), whereas in CBD (Flament et al., 1991; Ksiezak-Reding et al., 1994), PSP (Schmidt et al., 1996), and some FTDP-17 cases (Spillantini et al., 1997; Reed et al., 1998), only the 68 and 64 kDa bands are present. These biochemical data suggest that the isoform composition of the tau aggregates in these neurodegenerative tauopathies may be different from each other. Indeed, recent studies indicate that the 68 and 64 kDa insoluble tau bands in certain FTDP-17 cases are hyperphosphorylated 4R-tau isoforms only, and that the 3R-tau isoforms are spared (Spillantini et al., 1997; Reed et al., 1998; Clark et al., 1998; Hong et al., 1998). Since PSP and CBD manifest similar insoluble tau bands (Flament et al., 1991; Ksiezak-Reding et al., 1994; Schmidt et al., 1996), these 68 and 64 kDa bands also may contain 4R-tau isoforms alone, while the 64 and 60 kDa tau bands in Pick's disease may contain only 3R-tau (Sergeant et al., 1997; Delacourte et al., 1998). The implications of these findings is that abnormalities in factors determining the differential expression and/or functioning of the tau isoforms may underlie tau protein dysfunction and cause neurofibrillary lesion formation and neurodegeneration.
Defects in the tau gene have long been speculated to be the cause of several neurodegenerative diseases. For example, PSP is associated with an intronic microsatellite polymorphism in the tau gene (Conrad et al., 1997), and this polymorphism correlates with an excess of exon 10 containing tau mRNAs which encode 4R-tau (Chambers et al., 1998). More significantly, studies of FTDP-17 kindreds have demonstrated that tau gene mutations cause this autosomal dominant tauopathy (see below) which is characterized by diverse but overlapping clinical and neuropathological features (Bird et al., 1997; Foster et al., 1997; Heutink et al., 1997) and had been linked earlier to chromosome 17q21-22 (Wilhelmsen et al., 1994; Bird et al., 1997; Foster et al., 1997; Murrell et al., 1997; Heutink et al., 1997; Lendon et al., 1998). At least three distinct clinical syndromes have been described, namely pallido-ponto-nigral degeneration (PPND) (Wszolek et al., 1992; Wijker et al., 1996), disinhibition-dementia-parkinsonism-amyotrophy complex (DDPAC) (Lynch et al., 1994) and multiple system tauopathy with presenile dementia (MSTD) (Spillantini et al., 1997), but >20 FTDP-17 kindreds are known (Foster et al., 1997). Despite clinical heterogeneity, the postmortem brains of all FTDP-17 patients are characterized by the presence of numerous neuronal and glial inclusions that contain aggregated filaments formed from hyperphosphorylated tau proteins in association with marked neuronal loss (Reed et al., 1997; Spillantini et al., 1998; Reed et al., 1998; Spillantini et al., 1998).
Not surprisingly, tau gene mutations were suspected to cause FTDP-17, and >10 pathogenic mutations have been identified in the tau gene in >20 FTDP-17 kindreds. Among the first pathogenic mutations identified in the tau gene of FTDP-17 kindreds were the exonic G272V (Hutton et al., 1998), N279K (Clark et al., 1998), D280K (D'Souza et al., 1999; Rizzu et al, 1999), L284L (CTT to CTC) (D'Souza et al., 1999), P301L (Clark et al., 1998; Hutton et al., 1998), S305N (Iijima et al., 1998; D'Souza et al., 1999), V337M (Poorkaj et al., 1998), and R406W (Hutton et al., 1998) mutations (numbered according to the longest CNS tau isoform with 441 amino acids), and a group of intronic mutations in the 5 ? splice site of exon 10 (Spillantini et al., 1998; Hutton et al., 1998; D'Souza et al., 1999). These mutations are summarized in Table 2, but is likely that new mutations will continue to be discovered and this implies that FTDP-17 may be more prevelent than previously recognized.
E, exon; I, intron; R, MT-binding repeat; IR, inter-repeat region; N-term, amino-terminus; C-term, carboxy-terminus.
For a larger version of this table, click here.
Recent molecular and biochemical analyses suggest that these mutations may lead to tau protein dysfunction by two broad classes of mechanisms (Hutton et al., 1998; Hong et al., 1998; Hasegawa et al., 1998; D'Souza et al., 1999). First, the intronic mutations clustered around the 5 ? splice site of exon10 and some exonic mutations within exon 10, such as N279K, L284L, and S305N increase the 4R/3R tau ratio, which normally is ~1, by altering the splicing of exon10 (Hong et al., 1998; Hutton et al., 1998; D'Souza et al., 1999). This is supported by recent findings that there is an increased level of exon 10-containing tau mRNAs in the brains of FTDP-17 patients with intronic mutations (Hutton et al., 1998), and by exon-trapping assays which demonstrate a more frequent usage of the 5 ? splice site for exon 10 as a result of these mutations (Hutton et al., 1998; D'Souza et al., 1999). In addition, biochemical studies of FTDP-17 brains show that sarkosyl-insoluble tau extracted from DDPAC (E10+14), PPND (N279K), and MSTD (E10+3) brains contains only 4R-tau (Spillantini et al., 1998; Clark et al., 1998; Hong et al., 1998), and that the levels of 4R-tau are increased in both affected and unaffected regions of DDPAC and PPND brains (Hong et al., 1998).
The mechanisms by which these mutations alter exon 10 splicing and the 4R/3R tau ratio may involve multiple cis-acting elements (Spillantini et al., 1998; Hutton et al., 1998; D'Souza et al., 1999). For example, the intronic mutations may increase the inclusion of exon 10 in the transcripts by disrupting a putative inhibitory RNA stem-loop structure at the 5' splice site of exon 10 (Spillantini et al., 1998; Hutton et al., 1998). The N279K mutation may enhance an exon splicing enhancer (ESE) sequence (Xu et al., 1993; Watakabe et al., 1993; Lavigueur et al., 1993; Cooper and Mattox, 1997) when the nucleotide change from TAAGAA to GAAGAA increases the purine content in the GAR (R is a purine) repeats. The finding that the D280K mutation, which deletes 3 adjacent purines (AAG), abolishes exon 10 inclusion strongly supports this notion (D'Souza et al., 1999). In addition, an exon splicing silencing (ESS) element, which is predicted to suppress the inclusion of exon 10 (Si et al., 1998) can be destroyed when the sequence is changed from UUAG to UCAG by the silent L284L mutation (D'Souza et al., 1999), whereas the S305N mutation may cause over-splicing of exon 10 (D'Souza et al., 1999) by changing the normally weak GUgugagu 5 ? splice site to a stronger AUgugagu site (Senapathy et al., 1990). If the speculation is correct that 4R-tau and 3R-tau bind to distinct sites on MTs (Goode et al., 1997), then an increase in the 4R/3R tau ratio would result in an excess of intracytoplasmic unbound 4R-tau and an insufficient amount of 3R-tau to enable 3R-tau to function synergistically with 4R-tau to stabilize MTs, and the unbound 4R-tau would accumulate over time as insoluble aggregates followed by the dysfunction and death of neurons according to the hypothetical scenario outlined earlier.
Secondly, tau mutations may impair the ability of tau to bind to MTs and promote MT stability and assembly as suggested by data obtained from studies of the G272V, D280K, P301L, V337M and R406W mutations, but not the mutations that increase exon 10 splicing (Hong et al., 1998; Hasegawa et al., 1998; D'Souza et al., 1999). This loss of function could lead to an accumulation of non-functional mutant tau proteins in the cytoplasm. With time, the accumulated tau molecules could also aggregate into insoluble filaments, which composes of all six tau isoforms in the cases such as V337M and R406W, but only 4R-tau in the case of P301L (Clark et al., 1998; Hong et al., 1998) due to the exon 10 location of this mutation.
It is becoming increasingly clear that tau gene mutations cause FTDP-17 through mutation-specific perturbations leading to alterations in the expression, function and biochemistry of tau proteins, and it is plausible that similar mechanisms play a role in the onset/progression of other sporadic and inherited tauopathies. For example, tau hyperphosphorylation in sporadic AD leads to a complete loss of MT-binding by PHFtau which may destabilize MTs, disrupt axonal transport and comprise the function and viability of affected neurons which would be exacerbated by the accumulation of MT-binding-incompetent PHFtau into filamentous aggregates. The propensity for PHFtau to form filaments and aggregate is a toxic gain of function that is likely to be deleterious because it may lead to a physical obstruction of orthograde and retrograde intraneuronal transport. Thus, the loss of MT-binding-competent tau and the toxic space-occupying effect of PHFtau aggregates could act synergistically to cause the dysfunction and degenertation of affected neurons in sporadic AD and other non-genetic tauopathies. Therefore, it is becoming increasingly evident that tau dysfunction and the subsequent formation of neurofibrillary lesions from aggregated tau constitutes the central pathogenic pathway leading to brain degeneration in both sporadic and hereditary tauopathies, and new insights into these mechanisms are likely to emerge soon from studies of new cell culture and transgenic mouse models of tauopathies. Such insights are likely to have an important impact on other neurodegenerative disorders chracterized by abnormal protein-protein interaction that result in intracellular or extracellular accumulations of proteinaceous fibrils. For example, extracellular amyloid plaques containing aggregates of Ab peptide constitute another pathological hallmark of AD; intranuclear neuronal inclusions formed by the aggregation of mutant proteins harboring abnormally expanded polyglutamine tracts are characteristics of hereditary tri-nucleotide repeat disorders (Lieberman et al., 1998a); prion protein deposits are found in the brains of patients with sporadic or genetic form of spongiform encephalopathy (Lansbury, 1997); and Lewy bodies containing neurofilament subunits and a-synuclein are intracytoplasmic lesions in Parkinson's disease and diffuse Lewy body disease (Pollanen et al., 1993; Spillantini et al., 1997; Polymeropoulos et al., 1997; Wakabayashi et al., 1997; Baba et al., 1998; Irizarry et al., 1998; Spillantini et al., 1998; Takeda et al., 1998; Kruger et al., 1998). Thus, the aggregation of brain proteins into potentially toxic lesions is a common mechanistic theme in a diverse group of neurodegenerative diseases, and clarification of the pathogenic events in any of these disorders will have a profound impact on understanding the mechanisms that underlie all of these disorders and this may accelerate the discovery of more effective therapies for these neurodegenerative diseases.
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