Background: Tauopathies are a group of neurodegenerative disorders characterized by the pathological accumulation of hyperphosphorylated and insoluble tau protein within neurons and glia. Although most cases are sporadic, hereditary tauopathies have also been reported. Summary: In this article, we review genetic disorders in which tau pathology has been reported and present two novel families with primary tauopathies. Mutations in the microtubule-associated protein tau gene (MAPT) cause a small subset of primary tauopathies. Mutations in 21 other genes and an 18q deletion syndrome have also been reported to be associated with tau pathology reminiscent of Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease or Pick's disease. In 8 of the 21 genes, tau pathology was only seen in cases with some ‘specific' mutations. In the remaining genes, tau pathology, often in the form of Alzheimer-type neurofibrillary lesions, was a common finding but was ‘not mutation specific'. The probands of the two families were diagnosed with progressive supranuclear palsy based on clinicopathological evaluation. Their family histories were relevant for parkinsonism in 3 siblings of family 1 and 1 brother and the father from family 2, but these were not autopsy-confirmed. DNA from the brains of the probands from these families was screened for MAPT and leucine-rich repeat kinase 2 gene mutations, but no mutations were identified. Key Messages:MAPT mutations are a cause of familial tauopathies, but other genes have also been associated with tau pathology. Novel genes still await discovery.

Keywords:
Tauopathies, Genetics, Tau pathology, Microtubule-associated protein tau gene

Tauopathies are a group of neurodegenerative disorders with pathological accumulation of hyperphosphorylated and insoluble tau protein within neurons and glia [1]. In primary tauopathies tau inclusions are the major neuropathological abnormality, whereas in secondary tauopathies tau pathology occurs in association with other more specific pathology [2].

The tau protein promotes tubulin polymerization and stabilizes microtubules. Tau is encoded by the microtubule-associated protein tau gene (MAPT) on chromosome 17 [3]. Of 14 MAPT exons, exons 2, 3 and 10 undergo alternative splicing, and therefore, the mature tau proteins vary in size from 352 to 441 amino acids. Alternative splicing of exon 10 leads to two functionally different isoforms that contain either three or four 31-amino acid repeats depending on whether exon 10 is included (4R tau) or not (3R tau) [3]. Exon 10 encodes 1 of 4 tau microtubule-binding repeat regions; the remaining 3 are encoded by exons 9, 11 and 12. In normal adult human brains, the level of 3R isoforms is approximately equal to that of 4R isoforms [4]. Morphological and biochemical heterogeneity of the primary tauopathies is associated with the predominance of tau isoforms. This and the proportion of tau deposits within neurons or glial cells, together with the areas of the brain affected influence the clinical phenotype. The classical phenotypes of primary tauopathies correspond with the modern classification of frontotemporal lobar degeneration (FTLD) [5] and thus the term FTLD-tau can be applied [4]. These phenotypes include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), globular glial tauopathies (GGTs), argyrophilic grain disease (AGD), primary age-related tauopathy (PART), chronic traumatic encephalopathy (CTE), and frontotemporal dementia (FTD) with parkinsonism linked to chromosome 17 (FTDP-17) [4,6,7].

Based on the predominance of 3R/4R isoforms, tauopathies can be grouped into 4R tauopathies, including PSP, CBD, AGD, GGT and some forms of FTDP-17, while 3R tauopathies include PiD and some forms of FTDP-17 [4,7]. In PART, CTE, and some other forms of FTDP-17, there is a mixture of 3R and 4R tau pathology [7]. Neuronal lesions predominate in 3R tauopathies, while 4R tau accumulates in both neurons and glial cells [4,7]. Tau pathology can also differ depending on the conformational state of tau in neuronal Alzheimer-type paired helical filaments or Pick-type straight filaments [6].

The overwhelming majority of tauopathies occur sporadically, but tauopathies linked to MAPT mutations (i.e. FTDP-17) frequently share pathological and biochemical features with sporadic tauopathies [6,8]. Additionally, tau pathology has been reported in mutations in other genes. We review the genetics of tauopathies and describe two previously unpublished families with primary tauopathies.

We searched the PubMed database for all papers published in English that contained the words ‘familial' or ‘hereditary' and ‘tauopathies', ‘progressive supranuclear palsy', ‘corticobasal degeneration', ‘Pick's disease', ‘globular glial tauopathies', ‘argyrophilic grain disease' and ‘tauopathy-associated disorders'.

Genealogical, clinical and laboratory investigations were performed by means of medical chart review and telephone interviews with members of the two families. The probands of each family were neuropathologically diagnosed with tauopathy by an experienced neuropathologist (D.W.D.). DNA from the brains of the probands, which were stored in the Mayo Clinic Florida brain bank, was screened for mutations in all MAPT exons expressed in human brains (0-5, 7, 9-13) and LRRK2 exons 31 and 41, and flanking intronic regions using the Sanger sequencing method. The clinical study protocols were approved by the Mayo Clinic Institutional Review Board, and the autopsies were performed after approval by the next of kin or an individual with legal power of attorney.

Literature Review

More than 50 MAPT mutations have been reported in about 150 families with primary tauopathies (see http://www.molgen.ua.ac.be/ADMutations) [6], whereas the overwhelming majority of tauopathies occurs sporadically. This is also true for PSP, the most common primary tauopathy, which has an estimated prevalence of 5-6/ 100,000. Of all MAPT mutations, 10 have been associated with the phenotype of PSP, and 9 of these 10 mutations affected exon 10, increasing the expression of 4R tau isoforms [10].

Apart from MAPT mutations, deletion of part of the long arm of chromosome 18 as well as mutations in 21 other genes have been reported to occur with tau pathology. The tau pathology in these cases was reminiscent of that seen in Alzheimer's disease (AD), CBD, PSP, AGD or PiD and was often accompanied by deposition of other proteins, including α-synuclein, β- amyloid or TDP-43 (table 1). Tau protein has been reported to interact with some of these proteins, but the nature and type of these interactions are still a matter of debate. Results from some cellular research and animal models suggest that hyperphosphorylated tau protein is causally related with the activation of β-amyloid-induced microtubule disassembly and cell death. Other authors proposed alternative ways of interaction and suggested either the causative role of β-amyloid in tau pathology or synergistic toxic effects of both proteins [11]. β-Amyloid-induced oxidative stress is considered to be essential for tau hyperphosphorylation and subsequent neurofibrillary tangle (NFT) formation [12]. According to the tau axis hypothesis, progressively increasing concentrations of hyperphosphorylated tau in dendrites make neurons vulnerable to lesions caused by β-amyloid at the postsynaptic compartment. However, the process of tau hyperphosphorylation is driven by β-amyloid [11,12]. Tau has also been reported to interact with α-synuclein. Both proteins share some similarities. They are heat-stable, unfolded, contain characteristic repeats, and tau can also be present in Lewy bodies. Recent reports have shown that α-synuclein stimulates kinase-mediated phosphorylation of tau initiated by oxidative stress [12]. Prion proteins can also interact with tau by binding directly to tubulin and inhibiting tubulin oligomerization and, as a consequence, microtubule assembly [13].

In 8 of the 21 genes, tau pathology was detected in patients only with some ‘specific' mutations. In the remaining 12 genes (PSEN2, CNBP, SLC17A5, C9ORF72, ITM2B, NPC2, NPC1, CLN6, DMPK, PRNP, PANK2, APP), tau pathology in the form of Alzheimer-type NFTs was a common finding (table 1). Therefore we attributed this tauopathy to a nonspecific result of these mutations. Mutations of one gene, presenilin-1 (PSEN1), comprise both ‘specific' and ‘nonspecific' mutations with two different tauopathy phenotypes: AD and FTD. In the majority of the cases, it remains unclear what impact the primary mutation has on aggregation of tau protein and whether tau pathology is directly linked to these mutations or only an incidental finding.

In familial AD due to mutations in amyloid precursor protein (APP), PSEN1 or presenilin-2 (PSEN2) genes, accumulation of β-amyloid in senile plaques and amyloid angiopathy are considered to be the primary defects, but accumulation of hyperphosphorylated tau in NFTs, neuropil threads and dystrophic neurites in senile plaques is clearly involved in disease pathogenesis, and it is strongly linked to clinical phenotype [14]. Three PSEN1 mutations (p.M146L, p.M146V and p.G183V) have been reported to present with a clinical phenotype of FTD. At autopsy, the carriers of these mutations had neuronal inclusions reminiscent of Pick bodies [15,16,17]. Of note, the case with the p.G183V mutation showed only tau pathology but no extracellular amyloid deposits [15].

PSP-like pathology with substantia nigra globose NFTs and tufted astrocytes in the basal ganglia, but no significant neuronal loss in the subthalamic nucleus, was reported in the p.G2019S mutation in the leucine-rich repeat kinase 2 gene (LRRK2). Contrary to other LRRK2 mutation cases, there was no evidence of abnormal accumulation of α-synuclein, but only tau pathology in these particular patients with p.G2019S or p.R1441C mutations in LRRK2(table 1) [18,19]. Another LRRK2 mutation, p.R1441H, was reported in a patient with Parkinson's disease (PD) whose clinical manifestation evolved to PSP. However, the neuropathology was not reported [20].

The clinicopathological phenotype reminiscent of PSP was also reported in a patient with parkinsonism and vertical gaze palsy due to a p.C212Y mutation in the parkin (PRKN) gene. On autopsy, globose-type NFTs and tufted astrocytes were described but no Lewy bodies were identified. Although PRKN mutations have been associated with autosomal recessive, juvenile-onset PD, it is not unusual for there to be a lack of Lewy bodies or α-synuclein staining in cases with PRKN mutations [21]. PSP was also seen in four members of a Spanish family, and one of these cases was autopsy confirmed. Genetic testing did not show any MAPT mutations, but PSP was linked to 3.4 cM locus on chromosome 1q31.1 [9].

Tau pathology that resembled CBD was reported in patients with c.1012_1020del mutation of the solute carrier family 9, subfamily A (NHE6, cation proton antiporter 6), member 6 gene (SLC9A6). This included a variable degree of cortical and basal ganglia atrophy, coiled bodies and astrocytic plaques; however, severe degeneration of Purkinje cells and dentate nucleus and an absence of ballooned neurons differed from the classical CBD phenotype in these patients [22].

In a patient with a p.S115S mutation in the ATPase H+ transporting lysosomal accessory protein 2 gene (ATP6AP2), there were plaque-like structures in the striatum consisting of tau-positive glial processes similar to astrocytic plaques [23]. The latter are frequently seen in CBD, but in this patient they were limited in distribution, while more widespread in cortical and basal ganglia in CBD.

In patients with cerebrotendinous xanthomatosis caused by the p.R127W mutation in the cytochrome P450, family 27, subfamily A, polypeptide 1 gene (CYP27A1), tau pathology took the form of grains, tangles and coiled bodies that were predominantly found in the limbic system [24]. This phenotype is similar to that observed in sporadic AGD of the elderly.

Coexistence of the p.A239T variant of the MAPT gene and hexanucleotide expansions in C9ORF72 in a patient led to a clinicopathological phenotype of FTD without symptoms of motor neuron disease and with neuronal inclusions that were reminiscent of Pick bodies. The proband's 2 brothers were carriers of only the C9ORF72 mutation and developed amyotrophic lateral sclerosis, but not FTD [25].

Clinicopathological, Genealogical and Genetic Analysis of Two Families with Tauopathy

Family 1

The proband was a 79-year-old, right-handed woman with a 4-year history of a motor and cognitive disorder that initially presented with eye movement impairment. Later, she developed speech difficulties that were suggestive of progressive aphasia. She had backward falls, memory problems and episodes of anxiety. Two years before her death, neurological evaluation showed vertical gaze palsy, dysarthria and dysphagia. Motor signs included axial rigidity, retrocollis and limb spasticity. Brain computer tomography scans revealed moderate-to-marked atrophy of the brain, especially of the cerebellum, with prominent ventricles (table 2). Her family history was remarkable for parkinsonism in a brother and 2 sisters. No postmortem studies were available on other family members (fig. 1a).

The proband's calculated brain weight was 1,080 g. It had moderate cortical atrophy over the parasagittal superior frontal and superior parietal convexities. The subthalamic nucleus was slightly smaller than normal. There was no atrophy of the superior cerebellar peduncle. The substantia nigra had mild decreased pigmentation. Histologically, there was marked neuronal loss in the subthalamic nucleus and the substantia nigra. The motor cortex and the globus pallidus showed mild to moderate neuronal loss and gliosis. The cerebellum revealed patchy Purkinje cell loss and Bergmann gliosis in the vermis. The cerebellar dentate nucleus had focal neuronal loss and gliosis.

Alzheimer-type neurofibrillary pathology assessed with thioflavin S fluorescent microscopy was consistent with Braak NFT stage III (table 2). Neither senile plaques nor Lewy bodies were detected. Tau immunohistochemistry revealed a range of lesions, including pretangles, NFTs, tufted astrocytes, coiled bodies and neuropil threads (fig. 2). There was neither α-synuclein nor TDP-43 immunostaining present.

The overall pathological findings were those of a tauopathy most consistent with PSP, although cortical tau pathology was greater than usual. Involvement of the frontal cortex and the corticobulbar and corticospinal tracts correlated with clinical findings of dementia, dysphagia and limb spasticity.

Family 2

The proband was a right-handed man who died at the age of 69 years following a 9-year disease course. His first symptoms were parkinsonism and behavioral changes, including disinhibition, agitation, violent outbursts and increased libido.

Five years after symptom onset, he had difficulty multitasking, as well as visuoperceptual and visuospatial impairments. His language difficulties included reduced verbal fluency and impairments in motor speed and processing speed. The findings were consistent with primary progressive aphasia. Memory problems were also noted. On neurological examination he had axial rigidity, shuffling gait, postural instability with backward falls and hypophonia. He also had vertical gaze palsy, urinary incontinence and erectile dysfunction. 18F-fluorodeoxyglucose positron emission tomography showed decreased activity in anteromedial portions of both temporal lobes, which was worse on the left. There was no significant cortical atrophy.

Eight years after symptomatic onset he was wheelchair-bound and mute. He scored 22/30 on the Montreal Cognitive Assessment scale. There was no response to 75 mg/300 mg of carbidopa/levodopa therapy. Magnetic resonance imaging showed minimal periventricular white matter changes that were consistent with chronic microvascular ischemic changes. The cerebral sulci and prominent ventricles indicated volume loss. Molecular genetic analysis of transactivation response DNA binding protein (TARDBP) gene did not reveal any mutations.

The patient's family history was remarkable for PSP in a brother and parkinsonism in his father (fig. 1b). Neither diagnosis was pathologically confirmed.

The proband's calculated brain weight was 1,280 g. The cerebral hemisphere had a normal configuration, and the sulci and gyri showed no atrophy over the convexity. The periventricular white matter had patchy gray discoloration. The subthalamic nucleus was much smaller than normal. The infratentorial structures showed midbrain atrophy with dilation of the aqueduct, enlargement of the fourth ventricle and severe atrophy of the superior cerebellar peduncle. The substantia nigra had decreased pigmentation. The cerebellar sections showed marked atrophy of the dentate nucleus.

The neocortex had no significant neuronal loss or gliosis, except in the motor cortex where there was subjective neuronal loss. The globus pallidus revealed mild vascular calcification and mild gliosis. The thalamus had gliosis in the ventrolateral region. The subthalamic nucleus showed severe neuronal loss and gliosis, with severe neuronal and glial tau pathology. The thalamic fasciculus and internal capsule had many threads and coiled bodies. The substantia nigra showed marked neuronal loss in the ventrolateral cell group, but less neuronal loss in dorsal and medial cell groups. This was associated with extraneuronal neuromelanin, gliosis and neuronal and glial tau pathology. The cerebellum showed no significant Purkinje cell loss or Bergmann gliosis. The cerebellar dentate nucleus had severe neuronal loss and gliosis with severe grumose degeneration.

The Braak NFT stage was consistent with stage II-III (table 2). No senile plaques were present in the cortex or hippocampus. Tau immunohistochemistry revealed a range of lesions, including pretangles, NFTs, tufted astrocytes, coiled bodies and neuropil threads (fig. 2). There was neither α-synuclein nor TDP-43 immunostaining present.

The overall pathological findings were those of a primary tauopathy consistent with PSP, although oligodendroglial pathology was more marked than usual in both the forebrain and hindbrain structures.

Sequence analysis of the entire coding region of the MAPT gene identified no mutation in the probands of family 1 and family 2. Additional sequencing of LRRK2 exons 31 and 41 in both probands revealed no mutation at codons 1441 and 2019. Both probands were homozygous for the H1 MAPT haplotype.

MAPT mutations are a cause of familial tauopathies. However, the 18q deletion syndrome and mutations in 21 other genes may present with tau pathology, most frequently in the context of other well-defined pathologies. Importantly, while we aimed to provide a comprehensive overview of familial cases with known gene mutations and tau pathology, it remains unclear whether tau pathology is caused by the reported gene mutations or merely presents an incidental finding.

In our two families, the clinicopathological findings were consistent with primary tauopathies in the form of PSP. Molecular genetic analysis of all coding regions of MAPT did not bring clarification. Screening of the LRRK2 codons 1441 and 2019 that previously had been linked to the PSP phenotype [18,19] did not reveal any mutations. Despite a positive family history, we conclude that the lack of mutations in MAPT and LRRK2 suggests that unknown genetic factors and possibly mutations in new genes may play a role in the pathogenesis of familial tauopathies.

We thank Kelly E. Viola, ELS, for her editorial support. We would also like to thank Audrey J. Strongosky for her assistance with this project. This study was supported by the NIH P50NS072187 (D.W.D., Z.K.W.), the Max Kade Foundation (P.T.), an Allergan Medical Educational Grant (P.T.), a gift from Carl Edward Bolch Jr. and the Susan Bass Bolch Foundation (Z.K.W.), and Mayo Clinic Neuroscience Focused Research Team (Z.K.W.).

The authors have no conflicts of interest to declare.

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P.T. and M.S.-C. contributed equally to this work.

© 2015 S. Karger AG, Basel
2015
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