Broadening the phenotype of TARDBP mutations: the TARDBP Ala382Thr mutation and Parkinson’s disease in Sardinia

Mutations in the TARDBP gene are a cause of autosomal dominant amyotrophic lateral sclerosis (ALS) and of frontotemporal lobar degeneration (FTLD), but they have not been found so far in patients with Parkinson’s disease (PD). A founder TARDBP mutation (p.Ala382Thr) was recently identified as the cause of ~30% of ALS cases in Sardinia, a Mediterranean genetic isolate. We studied 327 consecutive Sardinian patients with clinically diagnosed PD (88 familial, 239 sporadic) and 578 Sardinian controls. One family with FTLD and parkinsonism was also included. The p.Ala382Thr heterozygous mutation was detected in eight unrelated PD patients (2.5%). The three patients from the FTLD/parkinsonism family also carried this mutation. Within the control group, there were three heterozygous mutation carriers. During follow-up, one of these individuals developed motoneuron disease and another, a rapidly progressive dementia; the third remains healthy at the age of 79 but two close relatives developed motoneuron disease and dementia. The eight PD patients carrying the p.Ala382Thr mutation had all sporadic disease presentation. Their average onset age was 70.0 years (SD 9.4, range 51–79), which is later but not significantly different from that of the patients who did not carry this mutation. In conclusion, we expand the clinical spectrum associated with TARDBP mutations to FTLD with parkinsonism without motoneuron disease and to clinically definite PD. The TDP-43 protein might be directly involved in a broader neurodegenerative spectrum, including not only motoneuron disease and FTLD but also PD

Association between Protective and Deleterious HLA Alleles with Multiple Sclerosis in Central East Sardinia

The human leukocyte antigen (HLA) complex on chromosome 6p21 has been unambiguously associated with multiple sclerosis (MS). The complex features of the HLA region, especially its high genic content, extreme polymorphism, and extensive linkage disequilibrium, has prevented to resolve the nature of HLA association in MS. We performed a family based association study on the isolated population of the Nuoro province (Sardinia) to clarify the role of HLA genes in MS. The main stage of our study involved an analysis of the ancestral haplotypes A2Cw7B58DR2DQ1 and A30Cw5B18DR3DQ2. On the basis of a multiplicative model, the effect of the first haplotype is protective with an odds ratio (OR) = 0.27 (95% confidence interval CI 0.13–0.57), while that of the second is deleterious, OR 1.78 (95% CI 1.26–2.50). We found both class I (A, Cw, B) and class II (DR, DQ) loci to have an effect on MS susceptibility, but we saw that they act independently from each other. We also performed an exploratory analysis on a set of 796 SNPs in the same HLA region. Our study supports the claim that Class I and Class II loci act independently on MS susceptibility and this has a biological explanation. Also, the analysis of SNPs suggests that there are other HLA genes involved in MS, but replication is needed. This opens up new perspective on the study of MS

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.

We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)

ICON Ethnography Group Workshop: Introduction to feathers (review)

Review of the ICON Ethnography Group Workshop: Introduction to feathers held at Birmingham Museum and Art Gallery, 17 -18 October 2007

Water in archaeological wood : a critical appraisal of some diagnostic tools for degradation assessment

Waterlogged wood conservation is ultimately directed towards effective drying of artefacts, since through this procedure is the best hope for their stabilisation. This is a much more risky activity for the conservator than it is for the modern timber technologist, because of the extreme chemical and physical changes the material has undergone during its burial. Nevertheless, we already have a number of adequately successful methods for the conservation of archaeological wood. What we don't have is all the information we might want for the modification of these techniques to provide fully predictable results for the widely variable material which comes in for treatment or for the economical treatment of large structures and bulk assemblages. The conservator's primary concerns are with permeability, diffusion rates, drying behaviour,and internal surface calculation, all of which depend on the wood's chemical preservation, and are mirrored in its sorption characteristics. Wood-water relations of archaeological material have not as yet received much attention from researchers, and the chemistry of this material only slightly more. The findings of wood science can not be assumed to apply to archaeological material where radical chemical change has significantly changed its properties. This thesis addresses this problem by providing a comprehensive and critical synthesis of past and current research from the fields of waterlogged wood conservation, wood technology, chemistry, and microbiology, wood degradation, and wood-water relations. One of the outcomes of this work was the bringing to light of evidence for a much greater role for anaerobic decay vectors than has up to now been acknowledged. This only serves to emphasise the very real need for more research in the water relations and degradation chemistry of archaeological waterlogged wood, and perhaps even more for research into the development of assessment techniques specifically designed for this material, and easy and inexpensive to apply for the practising conservator. This thesis investigates the development of such techniques and compiles a critical review of a number of the techniques already in common use by conservators and wood scientists. The designs for a simple, accurate sorption measuring apparatus are given, and the results from a large group of archaeological wood samples reported. From these results it is determined that the controlling factor in the water relations of this material appears to be bulk mass losses rather than changes to chemical constituent ratios. Alternative diagnostic tools which have the potential of obtaining indircct information about wood-water relations indirectly are also critically appraised. The results from bulk chemical analyses are compared to those from physical tests of density, moisture content and strength measurements. Results from Sibert resistance drill trials and polarising microscopy are appraised. Certain findings from these contradict some of the assumptions which underpin our models for calculating internal void space in archaeological waterlogged wood which are used in defining our conservation treatment approaches. Three techniques of instrumental analysis are also examined. The results from FFIR, Py-GC/MS, and elemental analysis reveal a number of useful and casily-recognisable markers for degradation. A series of important new markers for syringyl lignin degradation arise from this study. In the final appraisal, preference lies with these latter diagnostic tools, and arguments are provided for their greater accessibility to the conservator

Reidentifying the wood of the Queen Mary and Lamont harps

Identifying the wood of the surviving historical wire-strung harps of Ireland and Highland Scotland has long been an important goal of researchers and instrument-builders. In 1969, microscopic examination of the anatomical features of the wood of two of the earliest surviving harps of this type, the Queen Mary and Lamont of National Museums Scotland, identified all parts of both as European hornbeam (Carpinus betulus). Due to the importance of these two harps as early exemplars, this identification has had far-reaching implications for understanding the construction practices for this type of historical harp. Questions about the identification of the woods of the Queen Mary and Lamont harps have prompted a re-evaluation. In this article, we discuss the observations and evidence that led to our decision to reidentify the wood of both harps, including the use of X-ray computed tomography to test the earlier identification of all wooden members as the same species. A rigorous new identification has been undertaken that addresses the fragile state of the wood and the need to minimize the impact on these important musical artefacts by revising the sampling method and utilizing scanning electron microscopy as an alternative to conventional microscopic examination. The results of our work to date are presented, and the implications for these two harps and for other harps of this type are discussed