The Lived Experience of Nursing Students During Their Psychiatric Nursing Education: Does It Influence View of Psychiatric Nursing as a Career Choice?

Using a van Manen phenomenological approach combined with a Colaizzi step-wise data analysis procedure, this study seeks to describe the lived experience of recent nursing school graduates during their psychiatric didactic and clinical education and how the experience influenced their view of psychiatric nursing as a specialty choice. Inclusion criteria for participants were registered nurses (RN) who graduated from their entry level nursing program within the last three years; graduated from a United States RN program; and are currently working as an RN in an inpatient setting. Two groups of participants were selected; one group of nurses who chose psychiatric nursing as their first post-graduation employment after RN licensure and another group of nurses who did not choose psychiatric nursing as their first post-graduation employment. An overall essence of Quality of Exposure to Psychiatric Nursing was identified. Four main themes and five subthemes were identified: (1) fear & anxiety, (1a) unpredictability, (1b) external fear factors of friends & family, (2) clinical exposure, (2a) limited clinical time, (2b) negative role models, (2c) ambiguity of psych nurse skills & role, (3) peer & non-psych faculty not valuing psych, and (4) psych instructor teaching methods. A mitigating factor also emerged associated with all five participants who went into psychiatric nursing having psychiatric exposure prior to their nursing program. This study contributes to the overall science of nursing related to psychiatric nursing education. Studying this experience provides psychiatric instructors and schools of nursing the opportunity to develop learning experiences that foster future psychiatric nurses

Presenilin-1 mutations associated with familial Alzheimer’s disease do not disrupt protein transport from the endoplasmic reticulum to the Golgi apparatus

AbstractMutations in genes encoding presenilin-1 (PS1) and presenilin-2 (PS2) have been linked to familial forms of Alzheimer’s disease (AD). Cells expressing mutant presenilins produce elevated levels of Aβ42, the major amyloid peptide found in AD plaques. The mechanism whereby this occurs remains unknown, but the localization of presenilins to endoplasmic reticulum (ER) and Golgi compartments has suggested that they may function in intracellular trafficking pathways involved in processing β-amyloid precursor proteins (APP). To test this possibility, we coexpressed PS1(wt), PS1(M146L), or PS1(L286V) in HEK293 cells together with the LDL receptor, a classic glycoprotein marker that undergoes post-translational O-glycosylation in the Golgi compartment. Pulse-chase analysis of the receptor indicated that mutant presenilins had no effect on ER→Golgi transport. Similar results were obtained when the studies were carried out with cells expressing the Swedish variant of APP (SWAPP751) instead of the LDL receptor. Moreover, secretion of the soluble exodomain polypeptide fragments of SWAPP751 that arise from α-secretase and β-secretase cleavage was not markedly affected by the PS1 mutants. Despite the lack of discernible effect of the PS1 mutants on trafficking of proteins through the Golgi apparatus, they caused a substantial increase in the proportion of Aβ42 relative to total Aβ in the culture medium. The results suggest that mutant forms of PS1 cause elevated production of Aβ42 by a mechanism that is independent of a major disruption of exocytic trafficking of APP

Identification of Small Molecule Inhibitors of Tau Aggregation by Targeting Monomeric Tau As a Potential Therapeutic Approach for Tauopathies.

A potential strategy to alleviate the aggregation of intrinsically disordered proteins (IDPs) is to maintain the native functional state of the protein by small molecule binding. However, the targeting of the native state of IDPs by small molecules has been challenging due to their heterogeneous conformational ensembles. To tackle this challenge, we applied a high-throughput chemical microarray surface plasmon resonance imaging screen to detect the binding between small molecules and monomeric full-length Tau, a protein linked with the onset of a range of Tauopathies. The screen identified a novel set of drug-like fragment and lead-like compounds that bound to Tau. We verified that the majority of these hit compounds reduced the aggregation of different Tau constructs in vitro and in N2a cells. These results demonstrate that Tau is a viable receptor of drug-like small molecules. The drug discovery approach that we present can be applied to other IDPs linked to other misfolding diseases such as Alzheimer's and Parkinson's diseases.We thank the Wellcome Trust (UK), Medical Research Council (UK), Elan Pharmaceuticals (USA), the Canadian Institutes of Health Research (Canada) and the Alzheimer Society of Ontario (Canada), and Hungarian Brain Research Program (KTIA_NAP_13-2014-0009) for funding.This is the author accepted manuscript. The final version is available from Bentham Science via http://dx.doi.org/10.2174/15672050120915101910495

Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of a-Synuclein Protect Against Diverse a-Synuclein Mediated Dysfunctions

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease

Targeting the Intrinsically Disordered Structural Ensemble of a-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson's Disease

Abstract The misfolding of intrinsically disordered proteins such as a-synuclein, tau and the Ab peptide has been associated with many highly debilitating neurodegenerative syndromes including Parkinson's and Alzheimer's diseases. Therapeutic targeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a major challenge because of their heterogeneous conformational properties. We show here that a combination of computational and experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), that targets a-synuclein, a key protein in Parkinson's disease. We found that this compound has substantial biological activity in cellular models of a-synuclein-mediated dysfunction, including rescue of a-synuclein-induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount of a-synuclein targeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells. These results indicate that targeting a-synuclein by small molecules represents a promising approach to the development of therapeutic treatments of Parkinson's disease and related conditions

Passive Immunization Reduces Behavioral and Neuropathological Deficits in an Alpha-Synuclein Transgenic Model of Lewy Body Disease

Dementia with Lewy bodies (DLB) and Parkinson's Disease (PD) are common causes of motor and cognitive deficits and are associated with the abnormal accumulation of alpha-synuclein (α-syn). This study investigated whether passive immunization with a novel monoclonal α-syn antibody (9E4) against the C-terminus (CT) of α-syn was able to cross into the CNS and ameliorate the deficits associated with α-syn accumulation. In this study we demonstrate that 9E4 was effective at reducing behavioral deficits in the water maze, moreover, immunization with 9E4 reduced the accumulation of calpain-cleaved α-syn in axons and synapses and the associated neurodegenerative deficits. In vivo studies demonstrated that 9E4 traffics into the CNS, binds to cells that display α-syn accumulation and promotes α-syn clearance via the lysosomal pathway. These results suggest that passive immunization with monoclonal antibodies against the CT of α-syn may be of therapeutic relevance in patients with PD and DLB

Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions

Funder: Howard Hughes Medical Institute (HHMI); doi: https://doi.org/10.13039/100000011Abstract: The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson’s disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn. Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson’s disease