Cross-β helical filaments of Tau and TMEM106B in Gray and White Matter of Multiple System Tauopathy with presenile Dementia

Abstract

Background: The Microtubule-Associated Protein Tau (MAPT) is one of the proteins that are central to neurodegenerative diseases. The nature of intracellular tau aggregates is determined by the cell types whether neuronal or glial, the participating tau isoforms, and the structure of the amyloid filament. The transmembrane protein 106B (TMEM106B) has recently emerged as another significant player in neurodegeneration and aging. In the central nervous system, the composition of the gray and white matter differs considerably. The gray matter consists of nerve cell bodies, dendrites, unmyelinated axons, synaptic terminals, astrocytes, oligodendrocytes (satellite cells) and microglia. The white matter differs from the gray for the presence of axonal tracts as the only neuronal component and for the absence of nerve cell bodies, dendrites and synaptic terminals. Cryogenic electron microscopy (cryo-EM) studies have unveiled the structure of tau and TMEM106B, from the cerebral cortex, in several neurodegenerative diseases; however, whether tau and TMEM106B filaments from the gray and white matter share a common fold requires additional investigation. Methods: We isolated tau and TMEM106B from the cerebral cortex and white matter of the frontal lobes of two individuals affected by multiple system tauopathy with presenile dementia (MSTD), a disease caused by the MAPT intron 10 mutation +3. We used immunostaining, biochemical, genetics and cryo-EM methods to characterize tau and TMEM106B. Results: We determined that tau filaments in the gray and the white matter of MSTD individuals can induce tau aggregation and have identical AGD type 2 folds. TMEM106B amyloid filaments were also found in the gray and white matter of MSTD; the filament folds were identical in the two anatomical regions. Conclusions: Our findings show for the first time that in MSTD two types of amyloid filaments extracted from the gray matter have identical folds to those extracted from the white matter. Whether in this genetic disorder there is a relationship in the pathogenesis of the tau and TMEM106B filaments, remains to be determined. Furthermore, additional studies are needed for other proteins and other neurodegenerative diseases to establish whether filaments extracted from the gray and white matter would have identical folds.

TMEM106B C-terminal fragments aggregate and drive neurodegenerative proteinopathy

“…Due to the conflicting nature of these findings, the role of TMEM106B in neurodegeneration remains unclear. Recently, the C-terminal fragment of TMEM106B was demonstrated to form amyloid fibrils in the brains of patients across a diverse range of neurodegenerative diseases including AD and many ADRDs [12–14,16,66]. Furthermore, aggregation of this protein fragment has been observed in the brain naturally with age [15].…”

Criterios diagnósticos en la enfermedad demencial ¿Qué hay de nuevo?

“…La taupatía multisistémica con demencia presenil (multiple system tauopathy with presenile dementia -MSTD), causada por una mutación en la posición +3 del intrón 10 del gen MAPT (IVS10+3), se caracteriza por parálisis de la mirada vertical superior, desinhibición, bradicinesia y demencia progresiva Murrell et al, 1997;Spin et al, 2008;Hoq et al, 2023). Neuropatológicamente se hallan abundantes inclusiones filamentosas de tau 4R en neuronas y células gliales (astrocitos y oligodendrocitos) difusamente distribuidas en las sustancia gris y blanca del SNC.…”

Tau filaments with the Alzheimer fold in cases withMAPTmutations V337M and R406W

“…Mutations that cause the relative overproduction of wild-type 3R or 4R tau result in the deposition of 3R tau with the Pick fold (5) or 4R tau with the argyrophilic grain disease (AGD) fold (6). In cases of sporadic and familial tauopathies, filaments of TMEM106B also form in an age-related manner (7)(8)(9).…”