Taurelated Disorders

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Several neurodegenerative disorders appear to be related to the abnormal deposition of the micro-tubule-associated protein tau (MAPTau). A detailled discussion of this complex group of disorders is beyond the scope of this chapter. Excellent reviews on the clinical (58) and molecular (59) aspects of tauopathies have been published. The brief discussion here will be restricted to aspects directly related to their presentation as atypical parkinsonian syndromes.

Tau: Normal Function and Role in Disease

The normal function of tau is to bind to tubulin, to promote its polymerization, and to maintain the stability of microtubules. As also explained in other chapters of this book, the tau gene gives rise to six isoforms of the tau protein, generated by alternative splicing of exons 2, 3, and 10. Tau contains four imperfect repeat sequences in the carboxy terminal part of the protein, referred to as the micro-tubule binding domains. The fourth domain is encoded by exon 10. Therefore, alternative splicing of exon 10 determines whether the protein contains three or four copies of repeated sequence. Under normal conditions, three-repeat and four-repeat tau are present in roughly equal amounts in the brain.

Tau is found as fibrillar aggregates in AD (then called neurofibrillary tangles), but also in a number of other neurodegenerative disorders, such as PSP, CBD, the parkinsonism dementia complex of Guam, postencephalitic and posttraumatic parkinsonism, and others. The analysis of mutations of the tau gene and their functional consequences in inherited tauopathies has provided important information on the molecular mechanisms of tau-associated neurodegeneration.

Inherited Tauopathies With Mutations in the MAPTau Gene

The term "frontotemporal dementia with parkinsonism linked to chromosome 17," or FTDP-17, has been adopted for a familial disorder characterized by behavioral and cognitive disturbances, usually beginning between the ages of 40 and 50, progressing to dementia, and a variable degree of extrapyramidal, pyramidal, oculomotor, and lower motorneuron signs. Pathologically, atrophy of frontal and temporal lobes is most prominent, together with involvement of the substantia nigra, the amygdala, and the striatum (60). Only about 10% of all cases of frontotemporal dementia are inherited in an autosomal-dominant manner, but of these, a substantial subset of 10-40% turned out to be genetically linked to a locus on the long arm of chromosome 17 (17q21-22) (60,61). As the tau gene is located in this region, it had to be considered a primary candidate gene, and in fact, mutations in this gene have been identified (62) in many families with FTDP-17 (63).

Mutations are clustered around the part of the gene encoding the microtubule binding domain and have been found in exons 9, 10, 12, and 13, or in adjacent intronic sequences. The variability of the clinical phenotype is accounted for, at least in part, by the fact that tau mutations appear to lead to pathology by different mechanisms.

Intronic mutations flanking exon 10, as well as some exonic exon 10 mutations affect the alternative splicing of this exon, and as a consequence alter the relative abundance of three-repeat and four-repeat tau, the two major classes of the protein present in the brain (62). Other exon 10 and exon 9 mutations seem to impair the ability of tau to bind microtubules or to promote microtubule assembly, as shown by functional in vitro assays (64). Whereas mutations affecting exon 10 splicing lead to the deposition of predominantly four-repeat tau, non-exon 10 coding mutations result in tau aggregates consisting of three-repeat and four-repeat tau (65).

To some extent, the different functional consequences of the mutations result in a characteristic clinical picture. If mutations affect exon 10 splicing (and thus lead to the deposition of predominantly four-repeat tau) L-dopa unresponsive parkinsonism tends to be a a prominent clinical feature (66-68)

(reviewed in ref. 58). This is particularly striking in the family described by Wszolek et al. clinically and pathologically as pallido-ponto-nigral degeneration (PPND) (69). Affected subjects present with rapidly progressive L-dopa-unresponsive parkinsonism with supranuclear gaze palsy, with dementia, frontal-lobe release signs, and perseverative vocalizations developing later. This family was found to harbor a mutation (N279K) increasing the activity of an exoning splice enhancer of exon 10, thus leading to increased production of four-repeat tau (70,71).

However, behavioral disturbances may also be prominent in families with this class of mutations. In the first family linked to chromosome 17 (and in whom the disease had been named "disinhibition-dementia-parkinsonism-amyotrophy complex; see ref. 61) personality changes begin at an average age of 45, accompanied by hypersexuality and hyperphagia. L-dopa-unresponsive parkinsonism is a consistent feature. This family bears an intronic mutation adjacent to exon 10.

In other families, a more typical picture of frontotemporal dementia with cognitive and behavioral disturbances predominates, followed by parkinsonism, and other neurological disturbances such as supranuclear gaze palsy, pyramidal tract dysfunction, and urinary incontinence to a variable degree during the later course of the disease. These phenotypes are more commonly associated with missense mutations in the constitutively spliced exons 9, 12, and 13 (58). Other mutations have been associated with dementia with epilepsy (72), progressive subcortical sclerosis (73), or "familial multiple system tauopathy" (74).

The same mutation may lead to different clinical manifestations in different families and also within single pedigrees. The most common mutation, P301L, has been found to be associated with a variety of clinical phenotypes, more or less closely resembling Pick's disease (75), CBD (76), or PSP. The considerable variability within single families (77,78) indicates that other factors in addition to tau mutations are influencing the clinical characteristics of the disease in a given patient.

Although a reduced penetrance of tau mutations has been reported (62), heterozygous (dominant) mutations are almost exclusively found in individuals with a clearly positive dominant family history and are very rare in series of patients with sporadic dementing syndromes (< 0.2%) (79). However, recent evidence raises the possibility of autosomal-recessive mutations causing an apparently sporadic PSP-like phenotype (80) (see below).

The relationship between the tau gene, FTDP-17, and PSP is particularly interesting. As will be discussed below, typical PSP is nearly always a sporadic disorder, but the prominent accumulation of four-repeat tau strongly suggests that the tau protein, and hence possibly also the tau gene, is intimately involved in the disease process. Given the high variability of the clinical picture in families with tau mutations and the predominance of extrapyramidal symptoms associated with some of them, it is not too surprising that, as noted above, some tau mutations lead to a phenotype more or less resembling typical PSP. One interesting mutation causing a PSP-like phenotype, the S305S-muta-tion, is located in exon 10 of the tau gene and forms part of a stem-loop structure at the 5' splice donor site (81). Although the mutation does not give rise to an amino acid change in the tau protein, functional exon-trapping experiments show that it results in a significant 4.8-fold increase in the splicing of exon 10, resulting in the overproduction of tau containing four microtubule-binding repeats. Although the clinical phenotype in this family, as well as in other families with mutations that affect splicing of exon 10, share features of PSP, both clinically and neuropathologically, others have emphazised the differences that distinguish those families from typical PSP and have questioned whether the disorder should be called "familial PSP" (82). Regardless of terminology, this finding emphasizes the close relationship between FTDP-17 and PSP.

Another interesting observation strengthening this link is that in rare cases, homozygous or compound heterozygous mutations of the tau gene can cause a PSP-like syndrome (80,83), whereas heterozygous mutation carriers were either unaffected or showed only mild parkinsonism with late onset. Again, although this "recessive" form of FTDP-17 shared several features with PSP, both cases also differed from typical PSP by their early onset (40 yr or less) and by the presence of additional neurologic deficits, such as apraxia, cortical sensory deficits, or speech disturbances.

Other Diseases Associated With Tau Deposits

As in the synucleinopathies, the majority of cases of neurodegeneration with tau deposition is sporadic. Two disease entities are usually distinguished, but as will become apparent, are probably closely related: PSP and CBD.

Progressive Supranuclear Palsy (PSP)

PSP is a disease characterized by predominantly axial, L-dopa-unresponsive parkinsonism, early postural instability, supranuclear gaze palsy, and subcortical dementia (84).

PSP is, with exception of the cases described above, a sporadic disorder. It is pathologically characterized by the deposition of abnormally phosphorylized tau protein as neurofibrillary tangles and neuropil threads, consisting predominantly of four-repeat tau. Tangles are also present in astrocytes ("tufted astrocytes") and oligodendroglia (coiled bodies). Based on this pathologic pattern and on the insights gained into the molecular mechansisms from the inherited tauopathies described in the previous subheading, it seems likely that an abnormality of the splicing of the tau gene may be the underlying molecular defect.

Although no coding region or splice site mutations in the tau gene can be identified in typical PSP, there appears to be a genetic susceptibility to the disease that is related to the tau gene. Initially, Conrad and coworkers observed that one particular allele (which they called the "A0" allele) of a dinucleotide repeat marker within the tau gene is highly associated, in homozygous form, with PSP (85). This allele was later found to be part of an extended haplotype (the Hl-haplotype) of more than 100 kb, that is usually inherited en bloc (86,87). It is unclear why no recombinations occur within this region in the human population.

As the Hl-haplotype is common in the general population (~ 60% of chromosomes) it does per se not carry a high risk for the development of a tau-related disorder. It is possible, however, that a more recent mutation that has occurred on the background of this haplotype is responsible, or that the Hl-haplotype is merely "permissive" for the development of typical PSP, although the ultimate cause remains unknown.

Corticobasal Degeneration

Much of what has been said for PSP also holds true for CBD. CBD is in most instances a sporadic syndrome that shares with PSP the relentless progression of L-dopa-unresponsive parkinsonism and predominantly subcortical cognitive disturbances, but differs in the additional presence of a usually marked asymmetry of signs, dystonia and irregular reflex myoclonus in the most affected limb, as well as cortical sensory loss and, in about 40% of cases, the characteristic "alien limb sign." In addition to the subcortical changes, asymmetric cortical atrophy is often observed. Neuropathology reveals characteristic tau accumulation in the form of neuropil threads throughout gray and white matter. Tau filaments in CBD include both paired helical filament (PHF)-like filaments and straight tubules (59). As in PSP, the filaments are composed predominantly of four-repeat tau.

As was also described for PSP, in a few families with dominant tau mutations, the disease resembles CBD (76). It is probably a matter of semantics whether the disease in these cases should be called "familial CBD" or "FTDP resembling CBD," as long as it is kept in mind that there are similarities and differences: sporadic CBD is not caused by detectable exonic or splice site mutations in the tau gene, but it shares the same tau-related genetic background with PSP, the homozygocity for the Hl-haplotype, supporting the close relationship between these two disorders (88,89).

TAUOPATHIES, SYNUCLEINOPATHIES, AND BEYOND

Although recent genetic and pathologic evidence lead to the distinction of two major groups of neurodegenerative disorders, the tauopathies and the synucleinopathies, based on the predominant pathology and on mutations of the respective genes in rare familial forms of these diseases, there is also evidence accumulating that the pathogenic mechanisms may in fact be related.

As detailed above, there appears to be considerable overlap both clinically and pathologically between PD, DLB, and AD. Various combinations of Lewy pathology and AD-type pathology are found even in monogenically inherited forms.

However, there is also neuropathology and genetic evidence linking Lewy pathology to alterations of tau: LBs in DLB have been distinguished from LBs in PD by tau staining (22). Similarly, some LBs found in the brain of patients with the a-synuclein mutation A53T could be stained with antibodies to the tau protein (21).

An association of the H1 haplotype, which is present in homozygous form in the great majority of PSP-patients, with idiopathic PD has been reported (90) but not confirmed (91). However, in a total genome screen in a large number of sib pairs and small families with PD, the tau locus on chromosome 17 was identified as one of the five loci with suggestive lod scores (although not reaching statistical significance) (92).

Finally, in a recent report, Wszolek et al. describe a family with autosomal-dominant inheritance, initially presenting with pure L-dopa-responsive parkinsonism (93). Some affecteds progressed to show symptoms of atypical parkinsonism, including supranuclear gaze palsy. Interestingly, pathology in different members of this family varied, from typical brainstem LB disease to diffuse LB disease to a tauopathy resembling PSP (106). The gene locus in this family most likely maps to the PARK8 locus on chromosome 12. If in fact the disease in all affected subjects of this family is owing to a mutation in a single gene, this would bridge the gap between the two major categories of neurodegenerative disease recognized today, and strongly argue for a common pathogenic process.

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