Unclassified four-repeat tauopathy associated with familial parkinsonism and progressive respiratory failure

Abstract

We describe an autopsied patient with familial parkinsonism and unclassified four repeat-tau (4R-tau) aggregation. She presented with bradykinesia, truncal dystonia, and mild amnesia at the age of 61 and then exhibited body weight loss (15 kg over 8 months), sleep disturbances, and progressive respiratory failure with CO 2 narcosis. She died of respiratory failure at the age of 62, 14 months after disease onset. Her brother also showed parkinsonism at the age of 58 and suddenly died 6 months later. Postmortem examination revealed 4R-tau aggregation, which was characterized by neuronal globose-type tangles or pretangles, bush-like or miscellaneous astrocytic inclusions, and coiled bodies. The temporal tip, the striatum, the substantia nigra, the tegmentum of the midbrain, the medullary reticular formation, and the spinal cord were severely involved with tau aggregation. Argyrophilic grains and ballooned neurons were also found in the medial temporal structures, however, extensions of the 4R-aggregations in the case were clearly broader than those of the argyrophilic grains. Western blot analysis of sarkosyl-insoluble fractions from brain lysates revealed prominent bands of tau at both 33 kDa and 37 kDa. Genetic examinations did not reveal any known pathogenic mutations in MAPT, DCTN - 1, PSEN - 1, or familial or young-onset parkinsonism-related genes. The clinical manifestations, pathologic findings, and biochemical properties of aggregated tau in our patient cannot be explained by argyrophilic grain disease or other known 4R-tauopathies alone. Our results further extend the clinical and neuropathologic spectra of 4R-tauopathy.

Genetically engineered MAPT 10+16 mutation causes pathophysiological excitability of human iPSC-derived neurons related to 4R tau-induced dementia

“…As noted in the introduction, deposition of 4R tau aggregates is associated with a range of neurodegenerative disorders, such as progressive supranuclear palsy, corticobasal degeneration, FTDP-17, argyrophilic grain dementia, globular glial tauopathy, ageingrelated tau astrogliopathy, others [33][34][35][36]. Post-mortem studies have revealed tau aggregations throughout brain regions in a form of dense and prominent plagues, either neuronal or glial, distributed in equal measure in astrocytic processes and oligodendroglia [37][38][39]. After years of studying clinical cases and designing experimental models of tau pathology, more than 25 tau mutations have been identified to date [40], although the vast majority of the mutations remains unattributed to the known tau-related neurodegeneration causing dementia.…”

Tau interactome and RNA binding proteins in neurodegenerative diseases

“…However, in tauopathy it oligomerises and then forms aggregates with a range of conformations [ 38 ], resulting in distinct neuropathological lesions in each tauopathy [ 26 ]. Many tauopathies have a bias towards one tau isoform over the others [ 21 , 38 , 87 , 103 ] and the isoform of tau appears to influence the rate of aggregation with 4R isoforms aggregating the most rapidly [ 121 ]. It is not yet understood why this is the case.…”

Structure of the nonhelical filament of the Alzheimer’s disease tau core

“…In AD, ex vivo tau fibrils appear to be predominantly twisted, while nontwisting fibrils have not been documented. However, ribbon-like tau fibrils with no twist or only occasional twists have been reported in multiple system tauopathy with presenile dementia ( 40 ), in an unclassified 4R tauopathy associated with familial parkinsonism and progressive respiratory failure ( 41 ), and in an AD mouse model ( 42 ). Although the modern cryoEM technique is highly efficient for determining amyloid fibril structures, the technique requires fibril twists, thus nontwisting fibrils have largely escaped attention.…”