Perspectives of California Legislators on Institutional Barriers and Facilitators to Non-Partisan Research Evidence Use in State Health Policymaking.

BACKGROUND: Bridging the translational gap between research evidence and health policy in state legislatures requires understanding the institutional barriers and facilitators to non-partisan research evidence use. Previous studies have identified individual-level barriers and facilitators to research evidence use, but limited perspectives exist on institutional factors within legislatures that influence non-partisan research evidence use in health policymaking. OBJECTIVE: We describe the perspectives of California state legislators and legislative staff on institutional barriers and facilitators of non-partisan research evidence use in health policymaking and explore potential solutions for enhancing use. DESIGN: Case study design involving qualitative interviews. PARTICIPANTS: We interviewed 24 California state legislators, legislative office staff, and legislative research staff. APPROACH: Semi-structured recorded interviews were conducted in person or by phone to identify opportunities for enhancing non-partisan research evidence use within state legislatures. We conducted thematic analyses of interview transcripts to identify (1) when research evidence is used during the policymaking process, (2) barriers and facilitators operating at the institutional level, and (3) potential solutions for enhancing evidence use. RESULTS: Institutional barriers to non-partisan research evidence use in health policymaking were grouped into three themes: institutional policies, practices, and priorities. Interviews also revealed institutional-level facilitators of research evidence use, including (1) access and capacity to engage with research evidence, and (2) perceived credibility of research evidence. The most widely supported institutional-level solution for enhancing evidence-based health policymaking in state legislatures involved establishing independent, impartial research entities to provide legislators with trusted evidence to inform decision-making. CONCLUSIONS: Potential institutional-level changes within state legislatures may enhance evidence use in health policymaking, leading to improved health outcomes and lower healthcare costs for states.

Glucosylsphingosine Promotes α-Synuclein Pathology in Mutant GBA-Associated Parkinson's Disease.

Glucocerebrosidase 1 (GBA) mutations responsible for Gaucher disease (GD) are the most common genetic risk factor for Parkinson's disease (PD). Although the genetic link between GD and PD is well established, the underlying molecular mechanism(s) are not well understood. We propose that glucosylsphingosine, a sphingolipid accumulating in GD, mediates PD pathology in GBA-associated PD. We show that, whereas GD-related sphingolipids (glucosylceramide, glucosylsphingosine, sphingosine, sphingosine-1-phosphate) promote α-synuclein aggregation in vitro, glucosylsphingosine triggers the formation of oligomeric α-synuclein species capable of templating in human cells and neurons. Using newly generated GD/PD mouse lines of either sex [Gba mutant (N370S, L444P, KO) crossed to α-synuclein transgenics], we show that Gba mutations predispose to PD through a loss-of-function mechanism. We further demonstrate that glucosylsphingosine specifically accumulates in young GD/PD mouse brain. With age, brains exhibit glucosylceramide accumulations colocalized with α-synuclein pathology. These findings indicate that glucosylsphingosine promotes pathological aggregation of α-synuclein, increasing PD risk in GD patients and carriers.SIGNIFICANCE STATEMENT Parkinson's disease (PD) is a prevalent neurodegenerative disorder in the aging population. Glucocerebrosidase 1 mutations, which cause Gaucher disease, are the most common genetic risk factor for PD, underscoring the importance of delineating the mechanisms underlying mutant GBA-associated PD. We show that lipids accumulating in Gaucher disease, especially glucosylsphingosine, play a key role in PD pathology in the brain. These data indicate that ASAH1 (acid ceramidase 1) and GBA2 (glucocerebrosidase 2) enzymes that mediate glucosylsphingosine production and metabolism are attractive therapeutic targets for treating mutant GBA-associated PD.