China
Africa
Explore chapters and articles related to this topic
Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
Microscopic pathology shows: Numerous, large pale (achromatic) ballooned neurons in the basal ganglia and the motor and premotor cortex (layers III, V, and VI). These are intensely neurofilament protein positive (NFP+). These are not specific for CBD, but are found less prominently in PSP, Pick's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and AD.Neuropil threads: numerous and widespread threadlike processes in gray and white matter in the cortex, cerebral white matter, internal capsule, striatum, thalamic fasciculus, cerebral peduncle, and pons (Figures 16.59–16.61).Globose NFTs in the substantia nigra, locus ceruleus, and raphe nuclei.Pick's body–like tau inclusions in the cortex (layers II and III).Astrocytic plaques in focal atrophic cortices.Coiled bodies in oligodendrocytes (tau-positive fibers coiled around nucleus).Corticospinal tract degeneration.
Role of computational and structural biology in the development of small-molecule modulators of the spliceosome
Published in Expert Opinion on Drug Discovery, 2022
Riccardo Rozza, Pavel Janoš, Angelo Spinello, Alessandra Magistrato
Small-molecules targeting RNA have also been developed to tackle other diseases. For example, the gene encoding for the microtubule-associated protein tau (MAPT) can give rise to six isoforms of the tau protein. Alzheimer’s disease and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) have been associated with mutations in the regulatory pre-mRNA sequence of MAPT. These mutations, located 14 nts downstream of the exon 10 5’SS, alter the alternative splicing of MAPT pre-mRNA leading to the exon 10 inclusion and to an over-production of so-called 4 R tau isoform, which is aggregate-prone [112,113]. Small-molecule modulators, targeting the bulged adenosine (bulge-A) of the exon 10–intron RNA hairpin motif and thus inducing exon 10 skipping, have been identified [114,115]. NMR experiments and restrained MD simulations supplied a structural model for their binding to the MAPT RNA stem-mimic duplex, showing that these compounds stack in-between the GC base pairs surrounding the bulge-A and form H-bonds and/or stacking interactions with the neighboring bases. While the stacking interactions are necessary for the binding, the interaction with the surrounding bases is key for the sequence-specific targeting of bulge-A flanked by GC pairs. The most promising compound name as 9 in ref [114], when tested in a mouse-derived assay, showed activity in a μM range.
Genetics of frontotemporal dementia in China
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2021
Yaling Jiang, Bin Jiao, Xuewen Xiao, Lu Shen
MAPT was the first gene identified in families FTD, presented with parkinsonism together with cognitive and behavioral manifestations, which termed as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) (41). Mutations of MAPT are mainly clustered in exons9–12, encoding the four microtubule-binding domains of tau (42).