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Background: Although WD repeats domain 45 (WDR45) mutations have been linked to ß-propeller protein-associated neurodegeneration (BPAN), the precise molecular and cellular mechanisms behind this disease remain elusive. This study aims to shed light on the effects of WDR45-deficiency on neurodegeneration, specifically axonal degeneration, within the midbrain dopaminergic (DAergic) system. By examining pathological and molecular alterations, we hope to better understand the disease process. Methods: To investigate the effects of WDR45 dysfunction on mouse behaviors and DAergic neurons, we developed a mouse model in which WDR45 was conditionally knocked out in midbrain DAergic neurons (WDR45cKO). Through a longitudinal study, we assessed alterations in mouse behavior using open field, rotarod, Y-maze, and 3-chamber social approach tests. To examine the pathological changes in DAergic neuron soma and axons, we utilized a combination of immunofluorescence staining and transmission electron microscopy. Additionally, we performed proteomic analyses of the striatum to identify the molecules and processes involved in striatal pathology. Results: Our study of WDR45cKO mice revealed a range of deficits, including impaired motor function, emotional instability, and memory loss, coinciding with the profound loss of midbrain DAergic neurons. Prior to neuronal loss, we observed massive axonal enlargements in both the dorsal and ventral striatum. These enlargements were characterized by the accumulation of extensively fragmented tubular endoplasmic reticulum (ER), a hallmark of axonal degeneration. Additionally, we found that WDR45cKO mice exhibited disrupted autophagic flux. Proteomic analysis of the striatum in these mice showed that many differentially expressed proteins (DEPs) were enriched in amino acid, lipid, and tricarboxylic acid metabolisms. Of note, we observed significant alterations in the expression of genes encoding DEPs that regulate phospholipids catabolic and biosynthetic processes, such as lysophosphatidylcholine acyltransferase 1, ethanolamine-phosphate phospho-lyase, and abhydrolase domain containing 4, N-acyl phospholipase B. These findings suggest a possible link between phospholipid metabolism and striatal axon degeneration. Conclusions: In this study, we have uncovered the molecular mechanisms underlying the contribution of WDR45-deficiency to axonal degeneration, revealing intricate relationships between tubular ER dysfunction, phospholipid metabolism, BPAN and other neurodegenerative diseases. These findings significantly advance our understanding of the fundamental molecular mechanisms driving neurodegeneration and may provide a foundation for developing novel, mechanistically-based therapeutic interventions.
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Purpose: This study aims to identify the independent risk factors in the low anterior resection syndrome (LARS) after surgery for colorectal cancer (CRC). Method: This was a retrospective, single-institution study in the Second Affiliation Hospital of Dalian Medical University, China. Patients underwent sphincter-preserving low anterior resection with total or partial mesorectal resection (with or without protective ileostomy) and completed a self-filled questionnaire over the phone to assess postoperative bowel dysfunction from January 2017 to December 2019. The predictors of LAR were evaluated using univariate and multivariate analyses. Result: The study population was 566 patients, 264 (46.64%), 224 (39.58%), and 78 (13.78%) patients with no, minor, and major LARS, respectively. In the univariate analysis, independent factors such as tumor location and size, anastomotic height, protective ileostomy, post-operation chemoradiotherapy, tumor T stage, lymphatic nodal metastasis classification, surgery duration, and time interval for closure of stoma were significantly associated with LARS points while we found the tumor T stage and lymphatic nodal metastasis classification as the new independent risk factors compared with the last decade studies. In the multivariate analysis, factors such as low and middle tumor location and protective ileostomy, and post operation treatment, nodal metastasis classification were the independent risk factors for major LARS. Conclusion: The new independence risk factors were tumor T stage and lymphatic nodal metastasis status in univariate analysis in our study, with anastomotic height, low and middle tumor location, protective ileostomy, post-operation chemoradiotherapy, nodal metastasis status increasing LARS point in multivariate analysis after surgery for CRC.
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Background: The classical motor symptoms of Parkinson's disease (PD) are tightly linked to the gradual loss of dopamine within the striatum. Concomitantly, medium spiny neurons (MSNs) also experience morphological changes, such as reduced dendritic complexity and spine density, which may be potentially associated with motor dysfunction as well. Thus, MSNs may serve as the emerging targets for PD therapy besides the midbrain dopaminergic neurons. Results: To comprehensively examine pathological alterations of MSNs longitudinally, we established a TH Cre/ Pitx3 fl/fl (Pitx3cKO ) mouse model that developed canonical PD features, including a significant loss of SNc DAergic neurons and motor deficits. During aging, the targeted neurotransmitter, MSNs morphology and DNA methylation profile were significantly altered upon Pitx3 deficiency. Specifically, dopamine, GABA and glutamate decreased in the model at the early stage. While nuclear, soma and dendritic atrophy, as well as nuclear invaginations increased in the aged MSNs of Pitx3cko mice. Furthermore, more nuclear DNA damages were characterized in MSNs during aging, and Pitx3 deficiency aggravated this phenomenon, together with alterations of DNA methylation profiling associated with lipoprotein and nucleus pathway at the late stage. Conclusion: The early perturbations of the neurotransmitters within MSNs may potentially contribute to the alterations of metabolism, morphology and epigenetics within the striatum at the late stage, which may provide new perspectives on the diagnosis and pathogenesis of PD.
