Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia

A dynamic NMR study of 1,2-metallotropic shifts in trimethylplatinum(IV) halide complexes of 3-methylpyridazine.

3-Methylpyridazine (3-Mepydz) reacts with halogenotrimethylplatinum(IV), [PtXMe₃)₄], to afford complexes of type fac-[PtXMe₃(3-Mepydz)₂] (X = Cl, Br or I). In solution these complexes undergo 1,2-metallotropic shifts between the contiguous nitrogen donors producing different linkage isomers. Solution abundances of these ismers are strongly influenced by the steric effects of the 3-methyl group on the pyridazine ring, with the (1,1)-isomer always being predominant (≈ 95%). Activation energies for the fluxion were determined by variable temperature ¹H NMR spectroscopy, values of the (1,1) → (1,2) isomer shift being in the range 74–78 kJ mol⁻¹

Isolation and characterisation of the pyridazine (pydz) bridged halogenotrimethylplatinum(IV) complexes [(PtXMe₃)₂(μ-pydz)] (X = Cl, Br or I). X-Ray structure of [(PtIMe₃)₂(μ-pydz)]

The bridged dinuclear platinum(IV) complexes [(PtXMe₃)₂( μ-pydz)] (X = Cl, Br, I) were isolated as minor products from the reaction between pyridazine (pydz) and the halogenotrimethylplatinum(IV) tetramers. The X-ray crystal structure of the iodo complex reveals both a double halide bridge and a pyridazine bridged structure with a Pt Pt non-bonded distance of 3.5937(5) Å. The platinum atoms show only a slight deviation from an idealized octahedral geometry, but the structure is folded in the equatorial plane by 51.5° to accommodate the iodines between the two platinum moieties

Isolation and characterisation of the pyridazine (pydz) bridged halogenotrimethylplatinum(IV) complexes [(PtXMe₃)₂(μ-pydz)] (X = Cl, Br or I). X-Ray structure of [(PtIMe₃)₂(μ-pydz)]

The bridged dinuclear platinum(IV) complexes [(PtXMe₃)₂( μ-pydz)] (X = Cl, Br, I) were isolated as minor products from the reaction between pyridazine (pydz) and the halogenotrimethylplatinum(IV) tetramers. The X-ray crystal structure of the iodo complex reveals both a double halide bridge and a pyridazine bridged structure with a Pt Pt non-bonded distance of 3.5937(5) Å. The platinum atoms show only a slight deviation from an idealized octahedral geometry, but the structure is folded in the equatorial plane by 51.5° to accommodate the iodines between the two platinum moieties