Unraveling the complex role of MAPT-containing H1 and H2 haplotypes in neurodegenerative diseases.

A ~ 1 Mb inversion polymorphism exists within the 17q21.31 locus of the human genome as direct (H1) and inverted (H2) haplotype clades. This inversion region demonstrates high linkage disequilibrium, but the frequency of each haplotype differs across ancestries. While the H1 haplotype exists in all populations and shows a normal pattern of genetic variability and recombination, the H2 haplotype is enriched in European ancestry populations, is less frequent in African ancestry populations, and nearly absent in East Asian ancestry populations. H1 is a known risk factor for several neurodegenerative diseases, and has been associated with many other traits, suggesting its importance in cellular phenotypes of the brain and entire body. Conversely, H2 is protective for these diseases, but is associated with predisposition to recurrent microdeletion syndromes and neurodevelopmental disorders such as autism. Many single nucleotide variants and copy number variants define H1/H2 haplotypes and sub-haplotypes, but identifying the causal variant(s) for specific diseases and phenotypes is complex due to the extended linkage equilibrium. In this review, we assess the current knowledge of this inversion region regarding genomic structure, gene expression, cellular phenotypes, and disease association. We discuss recent discoveries and challenges, evaluate gaps in knowledge, and highlight the importance of understanding the effect of the 17q21.31 haplotypes to promote advances in precision medicine and drug discovery for several diseases.

Automated vision screening of children using a mobile graphic device.

BACKGROUND/OBJECTIVE: Can measuring interocular brightness disparity, acuity, and colour vision classify children with amblyopia? SUBJECTS/METHODS: Two hundred eight subjects (3-14 years) were recruited for a prospective, observational protocol to measure interocular brightness disparity, uniocular acuities with and without a pinhole, and colour vision using an iPad. Subjects looked through polarizing filters and chose the brighter of two spaceships to measure interocular brightness disparity. The differential brightness of image pairs was varied through a staircase algorithm until equal brightness was perceived. Acuities and colour vision were tested with tumbling Es and AO-HRR colour plates, respectively. Unilateral amblyopia was later confirmed in two subjects. RESULTS: Binocular brightness balance on the iPad detected amblyopes with 100% sensitivity and specificity. Using 20/30 as cutoff for normal acuity, 1 of the amblyopes was detected, and non-amblyopes were excluded by visual acuity pinhole testing. The mean difference between iPad and E-Chart visual acuities with pinhole was 0.02 logMAR with limits of agreement from -0.08 to +0.11 logMAR. iPad and printed plates Colour vision testing produced identical results. Testing times were brief and exit pleasure responses were positive. Mean and range testing times for Brightness Sense, Colour vision, and Visual Acuity were 32.7 s (range = 12-63 s), 52.8 min (range = 17-95 s), and 88.75 s (range = 41-188 s), respectively. CONCLUSIONS: Interocular brightness disparity, acuity, and colour vision can be measured in children as young as 3 years old solely through playing a game on a mobile device. Interocular brightness disparity is a sensitive and specific method to detect unilateral amblyopia.

Insoluble Tau From Human FTDP-17 Cases Exhibit Unique Transmission Properties In Vivo.

One hallmark of neurodegenerative diseases is the intracellular accumulation of hyperphosphorylated tau protein, a neuronal microtubule-associated protein, into structures known as neurofibrillary tangles. Tauopathies are heterogeneous neurodegenerative diseases caused by the misfolding of the tau protein. It has been previously shown that the tau protein can spread from cell to cell in a prion-like manner. Tauopathies can be sporadic or familial, with the identification of pathogenic mutations in the microtubule-associated protein tau gene on chromosome 17 in the familial cases. Different frontotemporal dementia with parkinsonism-17 (FTDP-17) cases are associated with varying clinical presentations and types of neuropathology. We previously demonstrated that insoluble tau extracted from sporadic tauopathy human brains contain distinct tau strains, which underlie the heterogeneity of these diseases. Furthermore, these tau strains seeded tau aggregates that resemble human tau neuropathology in nontransgenic and 6hTau mice in vivo. Here, we show insoluble tau from human brains of FTDP-17 cases transmit different patterns of neuronal and glial tau pathology in vivo, similar to the sporadic tauopathies. This suggests that each of these tau mutations has unique properties that underlie the heterogeneity of FTDP-17 cases.

Human tau pathology transmits glial tau aggregates in the absence of neuronal tau.

Tauopathies are characterized by abnormal accumulation of tau protein in neurons and glia. In Alzheimer's disease (AD), tau aggregates in neurons, while in corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), tau also aggregates in astrocytes and oligodendrocytes. We previously demonstrated that human CBD and PSP tauopathy lysates (CBD-tau and PSP-tau) contain distinct tau strains that propagate neuronal and glial tau aggregates in nontransgenic (nonTg) mouse brain. Yet the mechanism of glial tau transmission is unknown. Here, we developed a novel mouse model to knock down tau in neurons to test for glial tau transmission. While oligodendroglial tau pathology propagated across the mouse brain in the absence of neuronal tau pathology, astrocytic tau pathology did not. Oligodendroglial tau aggregates propagated along white matter tracts independently of neuronal axons, and resulted in oligodendrocyte cell loss. Thus, glial tau pathology has significant functional consequences independent of neuronal tau pathology.