Citations

AbstractBackgroundLoss of function mutations in PINK1 and PRKN are the most common causes of early‐onset Parkinson disease (PD). The encoded ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase PRKN together regulate the autophagic degradation of dysfunctional mitochondria, termed mitophagy. During this cytoprotective process, PINK1 and PRKN identify and jointly decorate damaged mitochondria with phosphorylated Ub (pS65‐Ub) that serves as the mitophagy tag. Accumulating evidence suggest a pathogenic role for impaired mitophagy in PD and related neurodegenerative conditions. This is in line with our previous finding of increased levels of the mitophagy marker pS65‐Ub in the hippocampus of postmortem Lewy body disease (LBD) brain.MethodWe performed a genome‐wide association study (GWAS) of hippocampal pS65‐Ub level to identify novel regulators of the PINK1‐PRKN‐directed mitophagy in LBD. In our two‐stage GWAS, we obtained 1,012 autopsy confirmed LBD samples (754 discovery stage, 258, replication stage) from Caucasian participants of European ancestry. Using an established, mostly automated workflow, hippocampal sections were immunostained for pS65‐Ub, scanned, and quantified with unbiased algorithms.ResultOur findings identified that APOE rs429358 (β: 0.50, 95% CI: 0.41 to 0.69, p = 8.67×10−25) was very strongly associated with pS65‐Ub levels in LBD brain. The APOE4 genotype is known to exacerbate Aβ and tau deposition. We did observe strong correlations of pS65‐Ub levels with both tau tangle and senile plaque density in the entire LBD cohort. Nevertheless, the increased pS65‐Ub levels in APOE4‐carrying LBD brains were also independent of Aβ and tau deposition in a subgroup (N = 175) with medium levels of these pathologies. To further explore APOE4 effects on mitophagy outside disease context, this observation was also confirmed in APOE‐targeted replacement mice and in induced pluripotent stem cell‐derived astrocytes.ConclusionOur findings nominate a novel mitophagy regulator in LBD brain and highlight a strong association of APOE4 with mitophagy alteration. Our results suggested that APOE4 may mediate mitophagy defects through two mechanisms, by aggravating Alzheimer’s‐type pathologies and also independent of them. With APOE4 being the strongest known risk factor for Alzheimer’s disease and dementia with Lewy bodies, our findings suggest a common mechanistic link underscoring the importance of mitochondrial quality control.

Abstract Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Abstract Glioblastoma is the most aggressive malignant brain tumor with the poor survival due to its invasive nature driven by cell migration. There is still no effective treatment targeting glioma cell migration based on their transcriptomic information, due to the lack of understanding in the links to the fundamental mechanics of cell migration. In the previous studies, we developed a physics-based motor-clutch model, the cell migration simulator (CMS), to identify the basic mechanisms of cell migration in various cell types. In this study, we found that glioblastoma patient-derived (xenograft) (PD(X)) cell lines across mesenchymal (MES), proneural (PN), classical (CL) subtypes and two institutions (N = 13 patients) had optimal motility and traction force on stiffnesses around 9.3kPa, with otherwise heterogeneous and uncorrelated motility, traction, and F-actin flow. We applied the CMS as a consistent framework to describe the physical parameters of glioblastoma patient cell migration. Using single cell migration and force generation data on compliant 2D surfaces, we found all glioma PD(X) lines (11 patients) had balanced myosin/adhesion ratios resulting in effective migration. Mesenchymal (MES) lines had enhanced F-actin polymerization resulting in higher motility. Adherent PDX lines had increased myosin-adhesion amount resulting in higher traction force. The CMS also predicted the differential cell migration under cytoskeletal drugs between glioma subtypes. Finally, we found 18 genes in actin cytoskeleton and focal adhesion pathways significantly correlated with the glioma physical parameters, which were being used to estimate the physical parameters of a larger cohort (66 patients) and to strategize targeting their cell migration. Overall, we described a consistent physics-based framework for parameterizing individual glioblastoma patients, connecting to clinical transcriptomic data, and predicting drug effects, that can potentially be used to develop subtype and patient-specific anti-migratory therapeutic strategies.

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross‐sectional and prospective association analyses of blood‐derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole‐genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P <0.01 was used for significance. We validated most of the previously reported associations between mtDNA CN and cardiovascular disease outcomes. For example, 1‐SD unit lower level of mtDNA CN was associated with 1.08 (95% CI, 1.04–1.12; P <0.001) times the hazard for developing incident CHD, adjusting for covariates. Mendelian randomization analyses showed no causal effect from a lower level of mtDNA CN to a higher CHD risk (β=0.091; P =0.11) or in the reverse direction (β=−0.012; P =0.076). Additional bidirectional Mendelian randomization analyses revealed that low‐density lipoprotein cholesterol had a causal effect on mtDNA CN (β=−0.084; P <0.001), but the reverse direction was not significant ( P =0.059). No causal associations were observed between mtDNA CN and obesity, diabetes, and hypertension, in either direction. Multivariable Mendelian randomization analyses showed no causal effect of CHD on mtDNA CN, controlling for low‐density lipoprotein cholesterol level ( P =0.52), whereas there was a strong direct causal effect of higher low‐density lipoprotein cholesterol on lower mtDNA CN, adjusting for CHD status (β=−0.092; P <0.001). Conclusions Our findings indicate that high low‐density lipoprotein cholesterol may underlie the complex relationships between mtDNA CN and vascular atherosclerosis.

Abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Surgery has long been an important treatment for limiting optic nerve damage and minimising visual loss in patients with glaucoma. Numerous improvements, modifications, and innovations in glaucoma surgery over recent decades have improved surgical safety, and have led to earlier and more frequent surgical intervention in glaucoma patients at risk of vision loss. This review summarises the latest advancements in trabeculectomy surgery, glaucoma drainage device (GDD) implantation, and minimally invasive glaucoma surgery (MIGS). A comprehensive search of MEDLINE, EMBASE, and CENTRAL databases, alongside subsequent hand searches—limited to the past 10 years for trabeculectomy and GDDs, and the past 5 years for MIGS—yielded 2283 results, 58 of which were included in the final review (8 trabeculectomy, 27 GDD, and 23 MIGS). Advancements in trabeculectomy are described in terms of adjunctive incisions, Tenon’s layer management, and novel suturing techniques. Advancements in GDD implantation pertain to modifications of surgical techniques and devices, novel methods to deal with postoperative complications and surgical failure, and the invention of new GDDs. Finally, the popularity of MIGS has recently promoted modifications to current surgical techniques and the development of novel MIGS devices.

The incidence of both cataract and glaucoma is increasing globally. With increasing patient expectation and improved technology, premium intraocular lenses (IOLs), including presbyopia-correcting and toric IOLs, are being increasingly implanted today. However, concerns remain regarding the use of premium IOLs, particularly presbyopia-correcting IOLs, in eyes with glaucoma. This systematic review evaluates the use of premium IOLs in glaucoma. A comprehensive search of the MEDLINE database was performed from inception until 1 June 2023. Initial search yielded 1404 records, of which 12 were included in the final review of post-operative outcomes. Studies demonstrated high spectacle independence for distance and good patient satisfaction in glaucomatous eyes, with positive outcomes also in post-operative visual acuity, residual astigmatism, and contrast sensitivity. Considerations in patient selection include anatomical and functional factors, such as the type and severity of glaucomatous visual field defects, glaucoma subtype, presence of ocular surface disease, ocular changes after glaucoma surgery, and the reliability of disease monitoring, all of which may be affected by, or influence, the outcomes of premium IOL implantation in glaucoma patients. Regular reviews on this topic are needed in order to keep up with the rapid advancements in IOL technology and glaucoma surgical treatments.