TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 1

Tibetan PHD2, an allele with loss-of-function properties

Tibetans have adapted to the chronic hypoxia of high altitude and display a distinctive suite of physiologic adaptations, including augmented hypoxic ventilatory response and resistance to pulmonary hypertension. Genome-wide studies have consistently identified compelling genetic signatures of natural selection in two genes of the Hypoxia Inducible Factor pathway, PHD2 and HIF2A. The product of the former induces the degradation of the product of the latter. Key issues regarding Tibetan PHD2 are whether it is a gain-of-function or loss-of-function allele, and how it might contribute to high-altitude adaptation. Tibetan PHD2 possesses two amino acid changes, D4E and C127S. We previously showed that in vitro, Tibetan PHD2 is defective in its interaction with p23, a cochaperone of the HSP90 pathway, and we proposed that Tibetan PHD2 is a loss-of-function allele. Here, we report that additional PHD2 mutations at or near Asp-4 or Cys-127 impair interaction with p23 in vitro. We find that mice with the Tibetan Phd2 allele display augmented hypoxic ventilatory response, supporting this loss-of-function proposal. This is phenocopied by mice with a mutation in p23 that abrogates the PHD2:p23 interaction. Hif2a haploinsufficiency, but not the Tibetan Phd2 allele, ameliorates hypoxia-induced increases in right ventricular systolic pressure. The Tibetan Phd2 allele is not associated with hemoglobin levels in mice. We propose that Tibetans possess genetic alterations that both activate and inhibit selective outputs of the HIF pathway to facilitate successful adaptation to the chronic hypoxia of high altitude

Frequency of LATE neuropathologic change across the spectrum of Alzheimer’s disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer’s disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese–American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia—broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with “frequent” neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aβ phase = 0 (lacking detectable Aβ plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer’s disease neuropathology

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1,131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (pvalue=4.82e-08, OR=2.12), and two known loci: UNC13A, led by rs1297319 (pvalue=1.27e-08, OR=1.50) and HLA-DQA2 led by rs17219281 (pvalue=3.22e-08, OR=1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n≥3) as compared to controls (n=0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g. DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis

Efficacy of Electronet Fencing for Excluding Coyotes: A Case Study for Enhancing Production of Black-Footed Ferrets

Reducing coyote (Canis latrans) predation can be an important management objective. Here, we evaluated the efficacy of electronet fencing for excluding coyotes from focal areas on black tailed prairie dog (Cynomys ludovicianus) colonies, measured the effect of fencing on wild-born black-footed ferret (Mustela nigripes) kit survival, and modeled costs and benefits of fencing. From 27 July to 2 October 2010 in northcentral Montana, USA, we erected and maintained 7.7 km of electronet that enclosed 108 ha on portions of 2 prairie dog colonies. We monitored 2 female ferrets and 6 kits inside exclosures and 3 females and 12 kits outside of exclosures. Percent of coyote sightings in the protected areas was 6 times less than expected during the exclosure period (42% pre-exclosure, 7% exclosure, 47% post-exclosure). We conclude that the electronet fencing was effective for dramatically decreasing coyote activity in focal areas where black-footed ferret litters were being raised.We found evidence that survival of kits living primarily in protected areas was 22% higher, but we qualify this finding because of low sample sizes and because our monitoring activity on the study site may have influenced coyote activity. We estimated one-time costs for fencing to be US$4,464/km and operation and/or maintenance costs for the 68 days of fence operation to be US$641/km. If fencing increased survival by 20–30%, then total cost per ferret kit not lost to coyote predation would range between US$5,400 and$3,600, or US$2,550 and$1,700 if fence set-up–take-down labor and use of an all-terrain vehicle were donated. Published 2013. This article is a U.S. Government work and is in the public domain in the USA

Efficacy of Electronet Fencing for Excluding Coyotes: A Case Study for Enhancing Production of Black-Footed Ferrets

ABSTRACT Reducing coyote (Canis latrans) predation can be an important management objective. Here, we evaluated the efficacy of electronet fencing for excluding coyotes from focal areas on black tailed prairie dog (Cynomys ludovicianus) colonies, measured the effect of fencing on wild-born black-footed ferret (Mustela nigripes) kit survival, and modeled costs and benefits of fencing. From 27 July to 2 October 2010 in northcentral Montana, USA, we erected and maintained 7.7 km of electronet that enclosed 108 ha on portions of 2 prairie dog colonies. We monitored 2 female ferrets and 6 kits inside exclosures and 3 females and 12 kits outside of exclosures. Percent of coyote sightings in the protected areas was 6 times less than expected during the exclosure period (42% pre-exclosure, 7% exclosure, 47% post-exclosure). We conclude that the electronet fencing was effective for dramatically decreasing coyote activity in focal areas where black-footed ferret litters were being raised. We found evidence that survival of kits living primarily in protected areas was 22% higher, but we qualify this finding because of low sample sizes and because our monitoring activity on the study site may have influenced coyote activity. We estimated one-time costs for fencing to be US$4,464/km and operation and/or maintenance costs for the 68 days of fence operation to be US$641/km. If fencing increased survival by 20-30%, then total cost per ferret kit not lost to coyote predation would range between US$5,400 and$3,600, or US$2,550 and$1,700 if fence set-up-take-down labor and use of an all-terrain vehicle were donated. Published 2013. This article is a U.S. Government work and is in the public domain in the USA

A multi-scale evaluation of pack stock effects on subalpine meadow plant communities in the Sierra Nevada

We evaluated the influence of pack stock (i.e., horse and mule) use on meadow plant communities in Sequoia and Yosemite National Parks in the Sierra Nevada of California. Meadows were sampled to account for inherent variability across multiple scales by: 1) controlling for among-meadow variability by using remotely sensed hydro-climatic and geospatial data to pair stock use meadows with similar non-stock (reference) sites, 2) accounting for within-meadow variation in the local hydrology using in-situ soil moisture readings, and 3) incorporating variation in stock use intensity by sampling across the entire available gradient of pack stock use. Increased cover of bare ground was detected only within "dry" meadow areas at the two most heavily used pack stock meadows (maximum animals per night per hectare). There was no difference in plant community composition for any level of soil moisture or pack stock use. Increased local-scale spatial variability in plant community composition (species dispersion) was detected in "wet" meadow areas at the two most heavily used meadows. These results suggest that at the meadow scale, plant communities are generally resistant to the contemporary levels of recreational pack stock use. However, finer-scale within-meadow responses such as increased bare ground or spatial variability in the plant community can be a function of local-scale hydrological conditions. Wilderness managers can improve monitoring of disturbance in Sierra Nevada meadows by adopting multiple plant community indices while simultaneously considering local moisture regimes