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Background: Intracytoplasmic inclusions comprised of aggregated alpha-synuclein (αsyn) represent a key histopathological feature of neurological disorders collectively termed "synucleinopathies," which includes Parkinson's disease (PD). Mutations and multiplications in the SNCA gene encoding αsyn cause familial forms of PD and a large body of evidence indicate a correlation between αsyn accumulation and disease. Decreasing αsyn expression is recognized as a valid target for PD therapeutics, with down-regulation of SNCA expression potentially attenuating downstream cascades of pathologic events. Here, we evaluated if Honokiol (HKL), a polyphenolic compound derived from magnolia tree bark with demonstrated neuroprotective properties, can modulate αsyn levels in multiple experimental models. Methods: Human neuroglioma cells stably overexpressing αsyn, mouse primary neurons, and human iPSC-derived neurons were exposed to HKL and αsyn protein and SNCA messenger RNA levels were assessed. The effect of HKL on rotenone-induced overexpression of αsyn levels was further assessed and transcriptional profiling of mouse cortical neurons treated with HKL was performed to identify potential targets of HKL. Results: We demonstrate that HKL can successfully reduce αsyn protein levels and SNCA expression in multiple in vitro models of PD with our data supporting a mechanism whereby HKL acts by post-transcriptional modulation of SNCA rather than modulating αsyn protein degradation. Transcriptional profiling of mouse cortical neurons treated with HKL identifies several differentially expressed genes (DEG) as potential targets to modulate SNCA expression. Conclusion: This study supports a HKL-mediated downregulation of SNCA as a viable strategy to modify disease progression in PD and other synucleinopathies. HKL has potential as a powerful tool for investigating SNCA gene modulation and its downstream effects.
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OBJECTIVE: There is reason to believe that introversion may relate to different patterns of negative and positive experiences in everyday life ("hassles" and "uplifts"), but there is little evidence for this based on reports made in daily life as events occur. We thus extend the literature by using data from ecological momentary assessments to examine whether introversion is associated with either the frequency or intensity of hassles and uplifts. METHOD: Participants (N = 242) were community-dwelling adults (63% Black, 24% Hispanic; ages 25-65; 65% women) who completed baseline measures of personality and mental health, followed by reports of hassles and uplifts 5x/day for 14 days. We present associations between introversion and hassles/uplifts both with and without controlling for mood-related factors (neuroticism, recent symptoms of depression, and anxiety). RESULTS: Introversion was associated with reporting less frequent and less enjoyable uplifts, but not with overall hassle frequency or unpleasantness; exploratory analyses suggest associations with specific types of hassles. CONCLUSIONS: Our results expand understanding of the role of introversion in everyday experiences, suggesting an overall association between introversion and uplifts (but not hassles, broadly) in daily life. Better understanding of such connections may inform future research to determine mechanisms by which introversion relates to health.
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Afecto , Estrés Psicológico , Adulto , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Estrés Psicológico/psicología , Introversión Psicológica , Ansiedad , Salud MentalRESUMEN
Although there is a strong association between depressive symptoms and markers of inflammation, it remains unclear whether depressive symptoms at one point in life may predict inflammation later in life. Moreover, despite extant literature linking sleep with both depressive symptoms and inflammation, there is little research investigating poor sleep as a mechanism linking depressive symptoms with later inflammation. The links between depression and physical health can also vary by gender. In longitudinal analyses with data from the Midlife in the United States (MIDUS) study, we examined whether depressive symptoms were associated with inflammatory markers 11 years later and whether these associations were mediated by sleep disturbances or moderated by gender. Participants reported depressive symptoms and demographic information at baseline. At 11-year follow-up, the same participants (n = 968) reported depressive symptoms, sleep quality and duration using validated scale items, and provided a blood sample from which inflammatory markers interleukin-6 (IL-6) and C-reactive protein (CRP) were quantified. Actigraphy assessment of sleep was obtained in a subsample (n = 276). After adjusting for concurrent depressive symptoms and other relevant covariates, baseline depressive symptoms were associated with CRP 11 years later in the full sample, and with IL-6 among women. Subjective sleep quality mediated the association between depressive symptoms and CRP. Results suggest that depressive symptoms may be longitudinally associated with inflammation; however, directionality issues cannot be determined from the present work, particularly as inflammation markers (which might have been associated with baseline depressive symptoms) were not available at baseline. Findings further suggest that longitudinal associations between depressive symptoms and inflammation may potentially be explained by sleep and may reflect gender specific patterns.
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Depresión , Interleucina-6 , Biomarcadores , Proteína C-Reactiva/metabolismo , Depresión/complicaciones , Femenino , Humanos , Inflamación/complicaciones , Estudios Longitudinales , Sueño , Calidad del Sueño , Estados UnidosRESUMEN
The DRM (Deese-Roediger-McDermott) paradigm produces robust false memories of non-presented critical words. After studying a thematic word list (e.g., bed, rest, and pillow) participants falsely remember the critical item "sleep." We report two false memory experiments. Study One introduces a novel use of the lexical decision task (LDT) to prime critical words. Participants see two letter-strings and make timed responses indicating whether they are both words. The word pairs Night-Bed and Dream-Thweeb both prime "sleep" but only one pair contains two words. Our primary purpose is to introduce this new methodology via two pilot experiments. The results, considered preliminary, are promising as they indicate that participants were as likely to recognize critical words (false memories) and presented words (true memories) just as when studying thematic lists. Study Two actually employs the standard DRM lists so that semantic priming is in play there as well. The second study, however, uses functional near-infrared spectroscopy (fNIRS) to measure activity in the prefrontal cortex during a DRM task which includes a deception phase where participants intentionally lie about critical lures. False and true memories occurred at high levels and activated many of the same brain regions but, compared to true memories, cortical activity was higher for false memories and lies. Accuracy findings are accompanied by confidence and reaction time results. Both investigations suggest that it is difficult to distinguish accurate from inaccurate memories. We explain results in terms of activation-monitoring theory and Fuzzy Trace Theory. We provide real world implications and suggest extending the present research to varying age groups and special populations. A nagging question has not been satisfactorily answered: Could neural pathways exist that signal the presence of false memories and lies? Answering this question will require imaging experiments that focus on regions of distinction such as the anterior prefrontal cortex.
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Conceptualizing physical pain and negative affect as potentially interactive, we hypothesized that higher levels of peripheral inflammatory markers would be observed consistently only among individuals with both higher negative affect and pain symptomatology. Participants were generally healthy midlife adults from the Bronx, NY (N â= â212, M age â= â46.77; 60.8% Black, 25.5% Hispanic/Latina/o) recruited as part of a larger study. Key measures were: reported pain intensity and pain interference at baseline, recent negative affect averaged from self-reports 5x/day for 7 days, and peripheral inflammatory markers (C-reactive protein [CRP] and a composite cytokine measure based on seven cytokines). Controlling for age, BMI, gender, and education, recent negative affect significantly interacted with both pain variables to explain variance in CRP, with higher CRP levels observed only in individuals with both higher negative affect and either higher pain intensity or pain interference. These findings contribute to an emerging literature suggesting that negative affect, pain, and inflammation are related in important and complex ways.
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BACKGROUND: Misfolding and aggregation of the presynaptic protein alpha-synuclein (αsyn) is a hallmark of Parkinson's disease (PD) and related synucleinopathies. Although predominantly localized in the cytosol, a body of evidence has shown that αsyn localizes to mitochondria and contributes to the disruption of key mitochondrial processes. Mitochondrial dysfunction is central to the progression of PD and mutations in mitochondrial-associated proteins are found in familial cases of PD. The sirtuins are highly conserved nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that play a broad role in cellular metabolism and aging. Interestingly, mitochondrial sirtuin 3 (SIRT3) plays a major role in maintaining mitochondrial function and preventing oxidative stress, and is downregulated in aging and age-associated diseases such as neurodegenerative disorders. Herein, we hypothesize that αsyn is associated with decreased SIRT3 levels contributing to impaired mitochondrial dynamics and biogenesis in PD. METHODS: The level of mitochondrial SIRT3 was assessed in cells expressing oligomeric αsyn within the cytosolic and mitochondrial-enriched fractions. Mitochondrial integrity, respiration, and health were examined using several markers of mitochondrial dynamics and stress response and by measuring the rate of oxygen consumption (OCR). Our findings were validated in a rodent model of PD as well as in human post-mortem Lewy body disease (LBD) brain tissue. RESULTS: Here, we demonstrate that αsyn associates with mitochondria and induces a decrease in mitochondrial SIRT3 levels and mitochondrial biogenesis. We show that SIRT3 downregulation is accompanied by decreased phosphorylation of AMPK and cAMP-response element binding protein (CREB), as well as increased phosphorylation of dynamin-related protein 1 (DRP1), indicative of impaired mitochondrial dynamics. OCR was significantly decreased suggesting a mitochondria respiratory deficit. Interestingly treatment with AMPK agonist 5-aminoimidazole-4-carboxamide-1-ß-d-ribofuranoside (AICAR) restores SIRT3 expression, improves mitochondrial function, and decreases αsyn oligomer formation in a SIRT3-dependent manner. CONCLUSIONS: Together, our findings suggest that pharmacologically increasing SIRT3 levels can counteract αsyn-induced mitochondrial dysfunction by reducing αsyn oligomers and normalizing mitochondrial bioenergetics. These data support a protective role for SIRT3 in PD-associated pathways and contribute significant mechanistic insight into the interplay of SIRT3 and αsyn.
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Mitocondrias/metabolismo , Enfermedad de Parkinson/metabolismo , Sirtuina 3/metabolismo , alfa-Sinucleína/metabolismo , Anciano , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Mitocondrias/patología , Enfermedad de Parkinson/patología , Ratas , Ratas Sprague-DawleyRESUMEN
This case report describes an individual with brain calcifications, cognitive decline, motor dysfunction, and hypocalcaemia. Exome sequencing revealed a previously reported variant in the CASR gene and a variant of uncertain significance in PDGFRB. The clinical phenotype is likely explained by the CASR variant, but we discuss how the PDGFRB variant could also participate in the phenotype.