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

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

An Empirical Analysis on Board Monitoring Role and Loan Portfolio Quality Measurement in Banks

This paper aims to analyze the effectiveness of the board monitoring role on specific loan portfolio quality measures in banks (default rate, recovery rate and provisioning rate). We use a sample comprises a totality of Italian-based banks, listed at Borsa Italiana SpA in 2006-2008 and a number of accounting proxies to express the loan portfolio quality of a bank. The results of the analysis show an overall weakness of the board role (expressed by Independents and Audit Committee on board) in monitoring loan portfolio quality of the bank, with the subsequent damage of the interests of stakeholders. A positive contribution of board monitoring, even if partial, is highlighted in two cases: Independents seems improve recovery rate, while the Audit committee enhances provisioning rate in banks. With reference to default rate, a total negative effect of board monitoring is reported. On the base of these results, some managerial implications are proposed

The determinant of reputational losses in banking

What determines reputational loss following operational losses in banking? The purpose of this paper is to empirically address this question. We estimate the reputational risk for a large sample of banks in Europe and the U.S. between 2003 and 2008. We have two main results. First, we provide evidence that there is the probability of reputational damage increases as profits and size increase. Second, we show that a higher level of capital invested and intangibles reduce the probability of reputational damag

The determinants of reputational risk in the banking sector

What determines reputational loss following operational losses in banking? The purpose of this paper is to empirically address this question. We estimate the reputational risk for a large sample of banks in Europe and the US between 2003 and 2008. We have two main results. First, we provide evidence that there is the probability that reputational damage increases as profits and size increase. Second, we show that a higher level of capital invested and intangible assets reduce the probability of reputational damag

Introduction

Corporate culture is a relatively new matter of interest for financial institutions. However, it deserves increasing attention within the more advanced academic debate, as well as among experts, professionals, and policy makers. Banks are realizing that culture is a sort of “missing link” in the understanding and governance of individual and social behaviors within corporate organizations, and that it has been long overlooked or taken for granted. At the same time, regulators, and supervisors are convincing themselves that sounder banking culture and conduct represent important value drivers also for other relevant stakeholders. In fact, the financial crisis was seriously exacerbated by an inadequate risk culture in the financial sector. In other words, there was a deep cultural problem under the decisions and behaviors that brought to the crisis. And several cases of misconduct and scandals can be fully explained only in light of the same cultural weaknesses in banks and other financial companies