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Heterozygous NKX2-1 loss-of-function variants cause combinations of hyperkinetic movement disorders (MDs, particularly childhood-onset chorea), pulmonary dysfunction, and hypothyroidism. Mobile element insertions (MEIs) are potential disease-causing structural variants whose detection in routine diagnostics remains challenging.To establish the molecular diagnosis of two first-degree relatives with clinically suspected NKX2-1-related disorder who had negative NKX2-1 Sanger (SS), whole-exome (WES), and whole-genome (WGS) sequencing.The proband's WES was analyzed for MEIs. A candidate MEI in NKX2-1 underwent optimized SS after plasmid cloning. Functional studies exploring NKX2-1 haploinsufficiency at RNA and protein levels were performed.A 347-bp AluYa5 insertion with a 65-bp poly-A tail followed by a 16-bp duplication of the pre-insertion wild-type sequence in exon 3 of NKX2-1 (ENST00000354822.7:c.556_557insAlu541_556dup) segregated with the disease phenotype.We identified a de novo exonic AluYa5 insertion causing NKX2-1-related disorder in SS/WES/WGS-negative cases, suggesting that MEI analysis of short-read sequencing data or targeted long-read sequencing could unmask the molecular diagnosis of unsolved MD cases. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome (CANVAS) is an autosomal recessive neurodegenerative disease characterized by adult onset and slowly progressive sensory neuropathy, cerebellar dysfunction, and vestibular impairment. In most cases, the disease is caused by biallelic (AAGGG)Fifteen individuals diagnosed with CANVAS and carrying only one heterozygous (AAGGG)We identified seven patients from five unrelated families with clinically defined CANVAS carrying a heterozygous (AAGGG)Our report expands the genotype spectrum of RFC1 disease. Full

The human genome expresses thousands of natural antisense transcripts (NAT) that can regulate epigenetic state, transcription, RNA stability or translation of their overlapping genes1,2. Here we describe MAPT-AS1, a brain-enriched NAT that is conserved in primates and contains an embedded mammalian-wide interspersed repeat (MIR), which represses tau translation by competing for ribosomal RNA pairing with the MAPT mRNA internal ribosome entry site3. MAPT encodes tau, a neuronal intrinsically disordered protein (IDP) that stabilizes axonal microtubules. Hyperphosphorylated, aggregation-prone tau forms the hallmark inclusions of tauopathies4. Mutations in MAPT cause familial frontotemporal dementia, and common variations forming the MAPT H1 haplotype are a significant risk factor in many tauopathies5 and Parkinson's disease. Notably, expression of MAPT-AS1 or minimal essential sequences from MAPT-AS1 (including MIR) reduces-whereas silencing MAPT-AS1 expression increases-neuronal tau levels, and correlate with tau pathology in human brain. Moreover, we identified many additional NATs with embedded MIRs (MIR-NATs), which are overrepresented at coding genes linked to neurodegeneration and/or encoding IDPs, and confirmed MIR-NAT-mediated translational control of one such gene, PLCG1. These results demonstrate a key role for MAPT-AS1 in tauopathies and reveal a potentially broad contribution of MIR-NATs to the tightly controlled translation of IDPs6, with particular relevance for proteostasis in neurodegeneration.

The decarbonization of the residential sector is fundamental for energy transition. In this context, it is promising the introduction of hydrogen in natural gas networks in specific hydrogen districts. Accordingly, hydrogen meters are needed for accounting the fuel consumptions. The topic of this work is the development and construction of an experimental apparatus for testing safely hydrogen volume and flow meters up to 24 m3/h (referred to standard conditions) in controlled environmental conditions, between -25 and +55 °C (and beyond). The apparatus realized can test up to four volume and flow meters in a climatic chamber while processing air or pure hydrogen or methane. Methane-hydrogen mixtures can be tested connecting simply bottles with synthetic blends. The aim is to verify the measurement accuracy of the meters under test. A dedicated data analysis protocol featuring statistical process control is developed to monitor the stability of the system during the test. It exploits statistical indicators representing the autocorrelation, the normality of residuals of the mean value and the lag plot. The apparatus is realized, and it complies with the leakage limits set by indications in literature. A new ultrasonic domestic meter is tested in the apparatus. It has been developed by Pietro Fiorentini S.p.A. in the framework of the Hy4Heat project. Its error trends measured at all temperatures comply with the limit of 3.5% between 0.12 and 2 m3/h and 2% between 2 and 20 m3/h, as imposed by legislations.

Viral vectors are rapidly being developed for a range of applications in research and gene therapy. Prototype foamy virus (PFV) vectors have been described for gene therapy, although their use has mainly been restricted to ex vivo stem cell modification. Here we report direct in vivo transgene delivery with PFV vectors carrying reporter gene constructs. In our investigations, systemic PFV vector delivery to neonatal mice gave transgene expression in the heart, xiphisternum, liver, pancreas, and gut, whereas intracranial administration produced brain expression until animals were euthanized 49 days post-transduction. Immunostaining and confocal microscopy analysis of injected brains showed that transgene expression was highly localized to hippocampal architecture despite vector delivery being administered to the lateral ventricle. This was compared with intracranial biodistribution of lentiviral vectors and adeno-associated virus vectors, which gave a broad, non-specific spread through the neonatal mouse brain without regional localization, even when administered at lower copy numbers. Our work demonstrates that PFV can be used for neonatal gene delivery with an intracranial expression profile that localizes to hippocampal neurons, potentially because of the mitotic status of the targeted cells, which could be of use for research applications and gene therapy of neurological disorders. Keywords: foamy virus, spumavirus, viral vector, gene therapy, vector tropism, bioimaging, hippocampus

Corticobasal degeneration typically progresses gradually over 5–7 years from onset till death. Fulminant corticobasal degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed corticobasal degeneration cases collected from 14 centres, we identified 6 RP-CBD cases (4.8%) who died of advanced disease within 3 years of onset. These RP-CBD cases had different clinical phenotypes including rapid global cognitive decline (N = 2), corticobasal syndrome (N = 2) and Richardson’s syndrome (N = 2). We also studied four corticobasal degeneration cases with an average disease duration of 3 years or less, who died of another unrelated illness (Intermediate-CBD). Finally, we selected 12 age-matched corticobasal degeneration cases out of a cohort of 110, who had a typical gradually progressive course and reached advanced clinical stage (End-stage-CBD). Quantitative analysis showed high overall tau burden (p = 0.2) and severe nigral cell loss (p = 0.47) in both the RP-CBD and End-stage-CBD groups consistent with advanced pathological changes, while the Intermediate-CBD group (mean disease duration = 3 years) had milder changes than End-stage-CBD (p p p = 0.02). In contrast to the predominance of astrocytic plaques we previously reported in preclinical asymptomatic corticobasal degeneration cases, neuronal tau aggregates predominated in RP-CBD exceeding those in Intermediate-CBD (anterior frontal cortex: p p = 0.001) and End-stage-CBD (anterior frontal cortex: p = 0.03, caudate: p = 0.01) as demonstrated by its higher neuronal-to-astrocytic plaque ratios in both anterior frontal cortex and caudate. We did not identify any difference in age at onset, any pathogenic tau mutation or concomitant pathologies that could have contributed to the rapid progression of these RP-CBD cases. Mild TDP-43 pathology was observed in three RP-CBD cases. All RP-CBD cases were men. The MAPT H2 haplotype, known to be protective, was identified in one RP-CBD case (17%) and 8 of the matched End-stage-CBD cases (67%). We conclude that RP-CBD is a distinct aggressive variant of corticobasal degeneration with characteristic neuropathological substrates resulting in a fulminant disease process as evident both clinically and pathologically. Biological factors such as genetic modifiers likely play a pivotal role in the RP-CBD variant and should be the subject of future research.

Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication facsstor C subunit 1 (RFC1) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG)(11) allele, does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia.

Late-onset ataxia is common, often idiopathic, and can result from cerebellar, proprioceptive, or vestibular impairment; when in combination, it is also termed cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). We used non-parametric linkage analysis and genome sequencing to identify a biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene as the cause of familial CANVAS and a frequent cause of late-onset ataxia, particularly if sensory neuronopathy and bilateral vestibular areflexia coexist. The expansion, which occurs in the poly(A) tail of an AluSx3 element and differs in both size and nucleotide sequence from the reference (AAAAG)11 allele, does not affect RFC1 expression in patient peripheral and brain tissue, suggesting no overt loss of function. These data, along with an expansion carrier frequency of 0.7% in Europeans, implies that biallelic AAGGG expansion in RFC1 is a frequent cause of late-onset ataxia.

Submitted by Kenia Bernini (kenia.bernini@ufpel.edu.br) on 2019-03-08T16:12:58Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Simone_Assis_Alves_Roberto_Dissertação.pdf: 6988537 bytes, checksum: cbdfd4198a6a49fc24027db26d21623a (MD5) Approved for entry into archive by Aline Batista (alinehb.ufpel@gmail.com) on 2019-03-18T16:36:46Z (GMT) No. of bitstreams: 2 Simone_Assis_Alves_Roberto_Dissertação.pdf: 6988537 bytes, checksum: cbdfd4198a6a49fc24027db26d21623a (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Approved for entry into archive by Aline Batista (alinehb.ufpel@gmail.com) on 2019-03-18T16:36:53Z (GMT) No. of bitstreams: 2 Simone_Assis_Alves_Roberto_Dissertação.pdf: 6988537 bytes, checksum: cbdfd4198a6a49fc24027db26d21623a (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Made available in DSpace on 2019-03-18T16:37:03Z (GMT). No. of bitstreams: 2 Simone_Assis_Alves_Roberto_Dissertação.pdf: 6988537 bytes, checksum: cbdfd4198a6a49fc24027db26d21623a (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-08-31 Sem bolsa A presente dissertação versa sobre uma etnografia junto a um coletivo de imigrantes senegaleses, que vivem (ou viveram) essa diáspora atual na cidade de Pelotas/RS. Propõe-se sistematizar um conjunto de experiências vivenciadas desde 2015, em que a observação participante se transformou e se intercalou, junto ao coletivo, no envolvimento direto, nos encaminhamentos e mediações perante o poder público local e organizações da sociedade civil, diante da forte repressão que esses imigrantes sofreram em suas atividades como vendedores ambulantes. Busca-se compreender as (re)configurações da identidade, por parte desses imigrantes, perante desse novo contexto, que em determinados momentos se apresenta a eles de forma hostil; as distintas representações que sobre eles recaem, advindas de diferentes segmentos da sociedade local; suas estratégias de inserção e as expectativas que os mobilizaram para um processo migratório; além de debater a construção dos discursos sobre legalidade e moralidade do trabalho no comércio ambulante desses imigrantes. Sendo assim, a fim de se (re)estabelecer novas (re)estruturações de saberes, práticas, representações e dinâmicas sociais, essa pesquisa antropológica visa não só contribuir para as políticas públicas, mas principalmente em futuras ações que venham a ser mais efetivas, propositivas e reflexivas Cette thèse porte sur une ethnographie d'un groupe d'immigrés sénégalais qui vivent (ou ont vécu) cette diaspora actuelle dans la ville de Pelotas/RS. Il est proposé de systématiser un ensemble d'expériences vécues depuis 2015, dans lesquelles l'observation participante a été transformée et intercalée, avec le collectif, dans la participation directe, dans les renvois et les médiations devant le pouvoir public local et les organisations de la société civile, face à la forte répression que ces immigrants ont souffert dans leurs activités de vendeurs de rue. Il cherche à comprendre la (re)configuration d'identité, de la part de ces immigrés, devant ce nouveau contexte, qui se présente à certains moments de manière hostile; les différentes représentations qui leur incombent, issues de différents segments de la société locale; leurs stratégies d'insertion et les attentes qui les ont mobilisées pour un processus de migration; outre discuter de la construction des discours sur la légalité et la moralité du travail dans le commerce itinérant de ces immigrés. Ainsi, afin de (re) mettre en place de nouvelles (re) structures de connaissances, de pratiques, de représentations et de dynamiques sociales, cette recherche anthropologique ne vise pas seulement à contribuer aux politiques publiques, mais principalement à des actions futures qui seront plus efficaces, propositionnel et réflexif.

TDP43 protein mislocalization is a hallmark of the neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia, and mutations in the gene encoding TDP43 cause both disorders, further highlighting its role in disease pathogenesis. TDP43 is a heterogenous ribonucleoprotein, therefore suggesting that alterations in RNA metabolism play a role in these disorders, although direct evidence in patients is lacking. Sporadic inclusion body myositis (sIBM) is the most common acquired myopathy occurring in adults aged older than 50 years and abnormal cytoplasmic accumulations of TDP43 have been consistently described in sIBM myofibers. Here, we exploit high quality RNA from frozen sIBM muscle biopsies for transcriptomic studies on TDP43-proteinopathy patient tissue. Surprisingly, we found widespread sIBM-specific changes in the RNA metabolism pathways themselves. Consistent with this finding, we describe novel RNA binding proteins to mislocalize in the cytoplasm of sIBM myofibers and splicing changes in MAPT, a gene previously shown to play a role in sIBM. Our data indicate widespread alterations of RNA metabolism are a novel aspect of disease pathogenesis in sIBM. These findings also document an association, in TDP43-proteinopathy patients, between heterogenous ribonucleoprotein pathology and RNA metabolism alterations and carry importance for neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal dementia.

Large-scale sequencing projects have revealed an unexpected complexity in the origins, structures and functions of mammalian transcripts. Many loci are known to produce overlapping coding and non-coding RNAs with capped 5′ ends that vary in size. Methods that identify the 5′ ends of transcripts will facilitate the discovery of novel promoters and 5′ ends derived from secondary capping events. Such methods often require high input amounts of RNA not obtainable from highly refined samples such as tissue microdissections and subcellular fractions. Therefore, we have developed nanoCAGE (Cap Analysis of Gene Expression), a method that captures the 5′ ends of transcripts from as little as 10 nanograms of total RNA and CAGEscan, a mate-pair adaptation of nanoCAGE that captures the transcript 5′ ends linked to a downstream region. Both of these methods allow further annotation-agnostic studies of the complex human transcriptome.

G-rich sequences in DNA and RNA have a propensity to fold into stable secondary structures termed G-quadruplexes. G-quadruplex forming sequences are widespread throughout the human genome, within both, protein coding and non-coding genes, and regulatory regions. G-quadruplexes have been implicated in multiple cellular functions including chromatin epigenetic regulation, DNA recombination, transcriptional regulation of gene promoters and enhancers, and translation. Here we will review the evidence for the occurrence of G-quadruplexes both in vitro and in vivo; their role in neurological diseases including G-quadruplex-forming repeat expansions in the C9orf72 gene in frontotemporal dementia and amyotrophic lateral sclerosis and loss of the G-quadruplex binding protein FMRP in the intellectual disability fragile X syndrome. We also review mounting evidence that supports a role for G-quadruplexes in regulating the processing or function of a range of non-coding RNAs. Finally we will highlight current perspectives for therapeutic interventions that target G-quadruplexes.

A comprehensive understanding of protein and regulatory networks is strictly dependent on the complete description of the transcriptome of cells. After the determination of the genome sequence of several mammalian species, gene identification is based on in silico predictions followed by evidence of transcription. Conservative estimates suggest that there are about 20 000 protein-encoding genes in the mammalian genome. In the last few years the combination of full-length cDNA cloning, cap-analysis gene expression (CAGE) tag sequencing and tiling arrays experiments have unveiled unexpected additional complexities in the transcriptome. Here we describe the current view of the mammalian transcriptome focusing on transcripts diversity, the growing non-coding RNA world, the organization of transcriptional units in the genome and promoter structures. In-depth analysis of the brain transcriptome has been challenging due to the cellular complexity of this organ. Here we present a computational analysis of CAGE data from different regions of the central nervous system, suggesting distinctive mechanisms of brain-specific transcription.

Background The mesencephalic dopaminergic (mDA) cell system is composed of two major groups of projecting cells in the Substantia Nigra (SN) (A9 neurons) and the Ventral Tegmental Area (VTA) (A10 cells). Selective degeneration of A9 neurons occurs in Parkinson’s disease (PD) while abnormal function of A10 cells has been linked to schizophrenia, attention deficit and addiction. The molecular basis that underlies selective vulnerability of A9 and A10 neurons is presently unknown. Results By taking advantage of transgenic labeling, laser capture microdissection coupled to nano Cap-Analysis of Gene Expression (nanoCAGE) technology on isolated A9 and A10 cells, we found that a subset of Olfactory Receptors (OR)s is expressed in mDA neurons. Gene expression analysis was integrated with the FANTOM5 Helicos CAGE sequencing datasets, showing the presence of these ORs in selected tissues and brain areas outside of the olfactory epithelium. OR expression in the mesencephalon was validated by RT-PCR and in situ hybridization. By screening 16 potential ligands on 5 mDA ORs recombinantly expressed in an heterologous in vitro system, we identified carvone enantiomers as agonists at Olfr287 and able to evoke an intracellular Ca2+ increase in solitary mDA neurons. ORs were found expressed in human SN and down-regulated in PD post mortem brains. Conclusions Our study indicates that mDA neurons express ORs and respond to odor-like molecules providing new opportunities for pharmacological intervention in disease. Electronic supplementary material The online version of this article (doi:10.1186/1471-2164-15-729) contains supplementary material, which is available to authorized users.

Odorous chemicals are detected by the mouse main olfactory epithelium (MOE) by about 1100 types of olfactory receptors (OR) expressed by olfactory sensory neurons (OSNs). Each mature OSN is thought to express only one allele of a single OR gene. Major impediments to understand the transcriptional control of OR gene expression are the lack of a proper characterization of OR transcription start sites (TSSs) and promoters, and of regulatory transcripts at OR loci. We have applied the nanoCAGE technology to profile the transcriptome and the active promoters in the MOE. nanoCAGE analysis revealed the map and architecture of promoters for 87.5% of the mouse OR genes, as well as the expression of many novel noncoding RNAs including antisense transcripts. We identified candidate transcription factors for OR gene expression and among them confirmed by chromatin immunoprecipitation the binding of TBP, EBF1 (OLF1), and MEF2A to OR promoters. Finally, we showed that a short genomic fragment flanking the major TSS of the OR geneOlfr160(M72) can drive OSN-specific expression in transgenic mice.

The mesencephalic dopaminergic (mDA) cell system is composed of two major groups of projecting cells in the substantia nigra (SN) (A9 neurons) and the ventral tegmental area (VTA) (A10 cells). A9 neurons form the nigrostriatal pathway and are involved in regulating voluntary movements and postural reflexes. Their selective degeneration leads to Parkinson's disease. Here, we report that gene expression analysis of A9 dopaminergic neurons (DA) identifies transcripts for α- and β-chains of hemoglobin (Hb). Globin immunoreactivity decorates the majority of A9 DA, a subpopulation of cortical and hippocampal astrocytes and mature oligodendrocytes. This pattern of expression was confirmed in different mouse strains and in rat and human. We show that Hb is expressed in the SN of human postmortem brain. By microarray analysis of dopaminergic cell lines overexpressing α- and β-globin chains, changes in genes involved in O 2 homeostasis and oxidative phopshorylation were observed, linking Hb expression to mitochondrial function. Our data suggest that the most famed oxygen-carrying globin is not exclusively restricted to the blood, but it may play a role in the normal physiology of the brain and neurodegenerative diseases.

Background A hexanucleotide expansion in C9orf72 is a common cause of the fatal neurodegenerative disorder amyotrophic lateral sclerosis. We have found evidence in a Drosophila model that neurotoxicity is mediated by dipeptide repeat (DPR) proteins generated by repeat-associated non-ATG translation. Here we aimed to evaluate in models of amyotrophic lateral sclerosis caused by the C9orf72 mutation ( C9orf72 -ALS) whether DPR proteins cause nucleolar dysfunction and whether novel small molecules that bind C9orf72 -repeat RNA reduce DPR formation and neurotoxicity. Methods We assessed nucleolar function in in-vivo Drosophila models. Nucleolar size was measured with immunofluorescence and confocal microscopy, using automated image analysis. Human induced pluripotent stem cells (iPSCs) from patients with C9orf72 -ALS and from healthy controls were taken through neural induction and patterning to derive spinal motor neuron populations. Disease phenotypes were measured with fluorescence in-situ hybridisation for the typical RNA foci seen in C9orf72 -ALS patients. Small molecules binding to C9orf72 -repeat RNA were fed to C9orf72 Drosophila and applied to the human iPSC-derived spinal motor neurons to evaluate rescue of disease phenotypes. Findings DPR proteins colocalised with nucleoli in C9orf72 - Drosophila brain tissue, with effects on nucleolar morphology. C9orf72 - Drosophila had significantly reduced egg-to-adult viability (p Drosophila was investigated. Interpretation Emerging evidence suggests that nucleolar dysfunction is a key mechanism in C9orf72 -ALS. It is crucial that this finding is validated in relevant disease models to rapidly translate findings into promising therapeutic targets. The high prevalence of C9orf72 -ALS makes use of targeted therapies a compelling strategy. These experiments might provide novel mechanistic insights into a common form of amyotrophic lateral sclerosis and deliver preclinical data on an exciting therapeutic approach. Funding RB is a Leonard Wolfson Clinical Research Training Fellow and is funded by a Wellcome Trust Clinical Research Training Fellowship (107196/Z/14/Z).

A comprehensive understanding of protein and regulatory networks is strictly dependent on the complete description of the transcriptome of cells. After the determination of the genome sequence of several mammalian species, gene identification is based on in silico predictions followed by evidence of transcription. Conservative estimates suggest that there are about 20 000 protein-encoding genes in the mammalian genome. In the last few years the combination of full-length cDNA cloning, cap-analysis gene expression (CAGE) tag sequencing and tiling arrays experiments have unveiled unexpected additional complexities in the transcriptome. Here we describe the current view of the mammalian transcriptome focusing on transcripts diversity, the growing non-coding RNA world, the organization of transcriptional units in the genome and promoter structures. In-depth analysis of the brain transcriptome has been challenging due to the cellular complexity of this organ. Here we present a computational analysis of CAGE data from different regions of the central nervous system, suggesting distinctive mechanisms of brain-specific transcription.

Progressive supranuclear palsy is a rare parkinsonian disorder with characteristic neurofibrillary pathology consisting of hyperphosphorylated tau protein. Common variation defining the microtubule associated protein tau gene (MAPT) H1 haplotype strongly contributes to disease risk. A recent genome-wide association study (GWAS) revealed 3 novel risk loci on chromosomes 1, 2, and 3 that primarily implicate STX6, EIF2AK3, and MOBP, respectively. Genetic associations, however, rarely lead to direct identification of the relevant functional allele. More often, they are in linkage disequilibrium with the causative polymorphism(s) that could be a coding change or affect gene expression regulatory motifs. To identify any such changes, we sequenced all coding exons of those genes directly implicated by the associations in progressive supranuclear palsy cases and analyzed regional gene expression data from control brains to identify expression quantitative trait loci within 1 Mb of the risk loci. Although we did not find any coding variants underlying the associations, GWAS-associated single-nucleotide polymorphisms at these loci are in complete linkage disequilibrium with haplotypes that completely overlap with the respective genes. Although implication of EIF2AK3 and MOBP could not be fully assessed, we show that the GWAS single-nucleotide polymorphism rs1411478 (STX6) is a strong expression quantitative trait locus with significantly lower expression of STX6 in white matter in carriers of the risk allele.

Microtubule-associated protein tau (MAPT) mutations have been shown to underlie frontotemporal dementia and a variety of additional sporadic tauopathies. We identified a rare p.A152T variant in MAPT exon 7 in two (of eight) patients with clinical presentation of parkinsonism and postmortem finding of neurofibrillary tangle pathology. Two siblings of one patient also carried the p.A152T variant, and both have progressive cognitive impairment. Further screening identified the variant in two other cases: one with pathologically confirmed corticobasal degeneration and another with the diagnosis of Parkinson's disease with dementia. The balance of evidence suggests this variant is associated with disease, but the very varied phenotype of the cases with the mutation is not consistent with it being a fully penetrant pathogenic mutation. Interestingly, this variation results in the creation of a new phosphorylation site that could cause reduced microtubule binding. We suggest that the A152T variant is a risk factor associated with the development of atypical neurodegenerative conditions with abnormal tau accumulation.

We report on the temperature dependent linewidth of the B 3u component of gn 1 mode in KClO 4 crystal measured by FTIR spectroscopy. These results are compared with previous ones obtained for the A g component. At temperatures higher then 80 K both components have a linear dependence on T showing that three-phonon scattering relaxation processes are driving the decay of this mode. The difference in the residual linewidths at low temperature (20 K) is interpreted in terms of different anharmonic couplings between the two componens and the thermal bath.