Showing papers by "Daniel L. Segal published in 2016"

The contribution of mutant GBA to the development of Parkinson disease in Drosophila

Abstract: Gaucher disease (GD) results from mutations in the acid β-glucocerebrosidase (GCase) encoding gene, GBA, which leads to accumulation of glucosylceramides GD patients and carriers of GD mutations have a significantly higher propensity to develop Parkinson disease (PD) in comparison to the non-GD population In this study, we used the fruit fly Drosophila melanogaster to show that development of PD in carriers of GD mutations results from the presence of mutant GBA alleles Drosophila has two GBA orthologs (CG31148 and CG31414), each of which has a minos insertion, which creates C-terminal deletion in the encoded GCase Flies double heterozygous for the endogenous mutant GBA orthologs presented Unfolded Protein Response (UPR) and developed parkinsonian signs, manifested by death of dopaminergic cells, defective locomotion and a shorter life span We also established transgenic flies carrying the mutant human N370S, L444P and the 84GG variants UPR activation and development of parkinsonian signs could be recapitulated in flies expressing these three mutant variantsUPR and parkinsonian signs could be partially rescued by growing the double heterozygous flies, or flies expressing the N370S or the L444P human mutant GCase variants, in the presence of the pharmacological chaperone ambroxol, which binds and removes mutant GCase from the endoplasmic reticulum (ER) However flies expressing the 84GG mutant, that does not express mature GCase, did not exhibit rescue by ambroxol Our results strongly suggest that the presence of a mutant GBA allele in dopaminergic cells leads to ER stress and to their death, and contributes to development of PD

Selective Inhibition of Aggregation and Toxicity of a Tau-Derived Peptide using Its Glycosylated Analogues.

Abstract: Protein glycosylation is a ubiquitous post-translational modification that regulates the folding and function of many proteins. Misfolding of protein monomers and their toxic aggregation are the hallmark of many prevalent diseases. Thus, understanding the role of glycans in protein aggregation is highly important and could contribute both to unraveling the pathology of protein misfolding diseases as well as providing a means for modifying their course for therapeutic purposes. Using β-O-linked glycosylated variants of the highly studied Tau-derived hexapeptide motif VQIVYK, which served as a simplified amyloid model, we demonstrate that amyloid formation and toxicity can be strongly attenuated by a glycan unit, depending on the nature of the glycan itself. Importantly, we show for the first time that not only do glycans hinder self-aggregation, but the glycosylated peptides are capable of inhibiting aggregation of the non-modified corresponding amyloid scaffold.

Naphthoquinone-Tryptophan Hybrid Inhibits Aggregation of the Tau-Derived Peptide PHF6 and Reduces Neurotoxicity.

Abstract: Tauopathies, such as Alzheimer's disease (AD), are a group of disorders characterized neuropathologically by intracellular toxic accumulations of abnormal protein aggregates formed by misfolding of the microtubule-associated protein tau. Since protein self-assembly appears to be an initial key step in the pathology of this group of diseases, intervening in this process can be both a prophylactic measure and a means for modifying the course of the disease for therapeutic purposes. We and others have shown that aromatic small molecules can be effective inhibitors of aggregation of various protein assemblies, by binding to the aromatic core in aggregation-prone motifs and preventing their self-assembly. Specifically, we have designed a series of small aromatic naphthoquinone-tryptophan hybrid molecules as candidate aggregation inhibitors of β -sheet based assembly and demonstrated their efficacy toward inhibiting aggregation of the amyloid-β peptide, another culprit of AD, as well as of various other aggregative proteins involved in other protein misfolding diseases. Here we tested whether a leading naphthoquinone-tryptophan hybrid molecule, namely NQTrp, can be repurposed as an inhibitor of the aggregation of the tau protein in vitro and in vivo. We show that the molecule inhibits the in vitro assembly of PHF6, the aggregation-prone fragment of tau protein, reduces hyperphosphorylated tau deposits and ameliorates tauopathy-related behavioral defect in an established transgenic Drosophila model expressing human tau. We suggest that NQTrp, or optimized versions of it, could act as novel disease modifying drugs for AD and other tauopathies.

Screening for Suicidal Thoughts and Behaviors in Older Adults in the Emergency Department.

Abstract: Objectives To estimate the prevalence of self-harm, suicidal ideation (SI), and suicide attempts (SA) in older adults in the emergency department (ED), including differences according to age, sex, and race and ethnicity. Design Quasi-experimental, multiphase, eight-center study with prospective review of consecutive charts during enrollment shifts (November 2011–December 2014). Setting Eight EDs in seven states, all with protocols for nurses to screen every patient for suicide risk (universal screening). Participants Adults (≥18 years) registered in the ED. Measurements Demographic characteristics; documented screening for self-harm, SI, or SA; and positive self-harm, SI, or SA in those with screening performed. Results Of 142,534 visits, 23.3% were of individuals aged 60 and older. Documented screening for self-harm, SI, or SA declined with age, from approximately 81% in younger age groups to a low of 68% in those aged 85 and older. The prevalence of positive screens for self-harm, SI, or SA also declined with age, with peaks in young and middle-age (9.0%) and reaching the lowest point after the age of 75 (1.2%). Conclusion Documented screening for suicide risk declined with age in this large sample of individuals in the ED. Although the reason for this finding is unclear, at least part of the decline may be related to increasing rates of altered mentation or other individual-level barriers to screening in the older population. These findings support the need for more-detailed examination of the best methods for identifying—and treating—suicide risk in older adults.

Assessment of Anxiety in Older Adults: Translation and Psychometric Evaluation of the German Version of the Geriatric Anxiety Scale (GAS)

Abstract: Anxiety occurs frequently among older adults, and can have deleterious impacts on the quality of daily life. Due to the dearth of well-validated elder-specific anxiety screening instruments available in the German language, this study aimed to translate the Geriatric Anxiety Scale (GAS), a reliable and valid 30-item self-report screening instrument for assessing anxiety based on DSM-IV-TR diagnostic criteria (Segal et al. Journal of Anxiety Disorders, 24(7), 709–714, 2010a), into German, and to validate the new measure. The German version of the GAS was developed through a translation and back translation process, with careful attention paid to culturally-sensitive expressions of anxiety in the German older adult population. The final version of the German GAS was tested in a sample of 242 community-dwelling older adults (Mage = 72.0 years, SD = 6.9 years; 59 % women) who completed either an online (26 %) or a paper-pencil (74 %) version of the questionnaire. The findings confirmed the successful translation of the GAS into German and provided psychometric support for the new measure. The validation of the factor structure based on confirmatory factor analyses was in support of a unidimensional structure of the GAS-G. Correlational analyses with inventories measuring anxiety related and non-anxiety related personality traits additionally confirmed the convergent and discriminant validity of the GAS for use as an assessment measure for anxiety among German older adults.

Deliberate self-harm among younger and older adults

Abstract: This study examined self-harming behaviors among younger and older adults who completed the Self-Harm Inventory (SHI). A 2 (age group) × 2 (gender) analysis of variance showed a significant main effect for age such that younger adult students (M = 3.42, SD = 3.86) had higher SHI total scores than community-dwelling older adults (M = 1.58, SD = 2.35). Younger adults endorsed “Yes” responses significantly more frequently than older adults on 13 of 22 items. Future research should examine specific behaviors of older adults who self-harm more frequently and explore relationships between self-harming behaviors and other risk and resiliency factors for elder suicide.