Background and Objectives Owing to the lack of long-term observations or comprehensive adjustment for confounding factors, reliable conclusions regarding long-term effects of exercise and regular physical activity in Parkinson disease (PD) have yet to be drawn. Here, using data from the Parkinson9s Progression Markers Initiative study that includes longitudinal and comprehensive evaluations of many clinical parameters, we examined the long-term effects of regular physical activity and exercise habits on the course of PD. Methods In this retrospective, observational cohort study, we primarily used the multivariate linear mixed-effects models to analyze the interaction effects of their regular physical activity and moderate to vigorous exercise levels, measured with the Physical Activity Scale for the Elderly questionnaire, on the progression of clinical parameters, after adjusting for age, sex, levodopa equivalent dose, and disease duration. We also calculated bootstrapping 95% confidence intervals (CIs) and conducted sensitivity analyses using the multiple imputation method and subgroup analyses using propensity score matching to match for all baseline background factors. Results Two hundred thirty-seven patients with early PD (median [interquartile range] age, 63.0 [56.0–70.0] years, male 69.2%, follow-up duration 5.0 [4.0–6.0] years) were included. Regular physical activity and moderate to vigorous exercise levels at baseline did not significantly affect the subsequent clinical progression of PD. However, average regular overall physical activity levels over time were significantly associated with slower deterioration of postural and gait stability (standardized fixed-effects coefficients of the interaction term [β_interaction] = −0.10 [95% CI −0.14 to −0.06]), activities of daily living (β_interaction = 0.08 [95% CI 0.04–0.12]), and processing speed (β_interaction = 0.05 [95% CI 0.03–0.08]) in patients with PD. Moderate to vigorous exercise levels were preferentially associated with slower decline of postural and gait stability (β_interaction = −0.09 [95% CI −0.13 to −0.05]), and work-related activity levels were primarily associated with slower deterioration of processing speed (β_interaction = 0.07 [95% CI 0.04–0.09]). Multiple imputation and propensity score matching confirmed the robustness of our results. Discussion In the long term, the maintenance of high regular physical activity levels and exercise habits was robustly associated with better clinical course of PD, with each type of physical activity having different effects. Trial Registration Information ClinicalTrials.gov Identifier: NCT01176565. Classification of Evidence This study provides Class II evidence that sustained increase in overall regular physical activity levels in patients with early PD was associated with slower decline of several clinical parameters.

Background and Objectives: This study aimed to identify CSF proteomic signatures characteristic of Parkinson disease (PD) and evaluate their clinical utility. Methods: This observational study utilized data from the Parkinson’s Progression Markers Initiative (PPMI), which enrolled PD patients, healthy controls (HCs), and non-PD participants carrying GBA1, LRRK2, and/or SNCA mutations (genetic-prodromals) at international sites. Study participants were chosen from PPMI enrollees based on the availability of aptamer-based CSF proteomic data, quantifying 4,071 proteins, and classified as patients with PD without GBA1, LRRK2, and/or SNCA mutations (non-genetic-PD), HCs, patients with PD carrying the aforementioned mutations (genetic-PD), or genetic-prodromals. Differentially expressed protein (DEP) analysis and the least absolute shrinkage and selection operator (LASSO) was applied to the data form non-genetic-PD and HCs. Signatures characteristics of non-genetic-PD were quantified as a PD proteomic score (PD-ProS), validated internally and then externally using data of 1,556 CSF proteins from the LRRK2 Cohort Consortium (LCC). We further tested the PD-ProS in genetic-PD and genetic-prodromals, and examined associations with clinical progression. Results: Data from 279 non-genetic-PD patients (mean ± standard deviation, age, 62.0 ± 9.6 years; male, 67.7%) and 141 HCs (age, 60.5 ± 11.9 years; male, 64.5%) were used for PD-ProS derivation. From 23 DEPs, LASSO determined weights of 14 DEPs for the PD-ProS (area under the curve [AUC] = 0.83 [95% confidence interval (CI), 0.78–0.87]), validated in an independent internal validation cohort of 71 non-genetic-PD patients and 35 HCs (AUC=0.81 [95% CI, 0.73–0.90]). In the LCC, only 5 of the 14 DEPs were also measured. Importantly, these 5 DEPs still distinguished 31 non-genetic-PD patients from 34 HCs with the same weights (AUC = 0.75 [95% CI, 0.63–0.87]). Furthermore, the PD-ProS distinguished 258 genetic-PD patients from 365 genetic-prodromals. Finally, regardless of genetic status, the PD-ProS independently predicted both cognitive and motor decline in PD (dementia, adjusted hazard ratio in the highest quintile (aHR-Q5) = 2.8 [95% CI, 1.6–5.0]; Hoehn and Yahr stage IV, aHR-Q5 = 2.1 [95% CI, 1.1–4.0]). Discussion: By integrating high-throughput proteomics with machine learning, we identified PD-associated CSF proteomic signatures crucial for PD development and progression. Trial Registration Information: Clinicaltrials.gov (NCT01176565). A link to the trial registry page is https://clinicaltrials.gov/ct2/show/NCT01141023. Classification of Evidence: This study provides Class II evidence that the CSF proteome contains clinically important information regarding the development and progression of Parkinson disease that can be deciphered by a combination of high-throughput proteomics and machine learning.

Liquid-liquid phase separation (LLPS) is involved in various dynamic biological phenomena. In epithelial cells, dynamic regulation of junctional actin filaments tethered to the apical junctional complex (AJC) is critical for maintaining internal homeostasis against external perturbations; however, the role of LLPS in this process remains unknown. Here, after identifying a multifunctional actin nucleator, cordon bleu (Cobl), as an AJC-enriched microtubule-associated protein, we conducted comprehensive in vitro and in vivo analyses. We found that apical microtubules promoted LLPS of Cobl at the AJC, and Cobl actin assembly activity increased upon LLPS. Thus, microtubules spatiotemporally regulated junctional actin assembly for epithelial morphogenesis and paracellular barriers. Collectively, these findings established that LLPS of the actin nucleator Cobl mediated dynamic microtubule-actin cross-talk in junctions, which fine-tuned the epithelial barrier.

Apical constriction is critical for epithelial morphogenesis, including neural tube formation. Vertebrate apical constriction is induced by di‐phosphorylated myosin light chain (ppMLC)‐driven contraction of actomyosin‐based circumferential rings (CRs), also known as perijunctional actomyosin rings, around apical junctional complexes (AJCs), mainly consisting of tight junctions (TJs) and adherens junctions (AJs). Here, we revealed a ppMLC‐triggered system at TJ‐associated CRs for vertebrate apical constriction involving microtubules, LUZP1, and myosin phosphatase. We first identified LUZP1 via unbiased screening of microtubule‐associated proteins in the AJC‐enriched fraction. In cultured epithelial cells, LUZP1 was found localized at TJ‐, but not at AJ‐, associated CRs, and LUZP1 knockout resulted in apical constriction defects with a significant reduction in ppMLC levels within CRs. A series of assays revealed that ppMLC promotes the recruitment of LUZP1 to TJ‐associated CRs, where LUZP1 spatiotemporally inhibits myosin phosphatase in a microtubule‐facilitated manner. Our results uncovered a hitherto unknown microtubule‐LUZP1 association at TJ‐associated CRs that inhibits myosin phosphatase, contributing significantly to the understanding of vertebrate apical constriction.