Biology subjects

Lindholm, D.

Publications and source records attributed to Lindholm, D..

5 recordsLinked to original sources

bioRxiv2024

USP14 regulates pS129 α-synuclein levels and oxidative stress in human SH-SY5Y dopaminergic cells

Ubiquitin specific protease-14 (USP14) is critical for controlling protein homeostasis disturbed in human disorders like Parkinso[n]s disease (PD). Here we investigated the role of USP14 in regulating proteasome and autophagy pathways, and their influence on -synuclein (-syn) degradation. Data showed that -syn and phosphorylated serine129 -syn (pS129 -syn) were elevated in USP14 gene-deleted SH-SY5Y dopaminergic cells with concomitant reduction in proteasome activity. Inhibition of proteasomes using MG132 particularly elevated pS129 -syn in these cells, but the levels were not influenced by inhibiting autophagy using chloroquine. In contrast, autophagy and the CLEAR (Coordinated Lysosomal Expression and Regulation) pathways were elevated in USP14 lacking cells with an upregulation of the transcription factor TFEB. USP14-ablated cells also exhibited increases in reactive oxidative species (ROS) and elongation of mitochondria. The addition of N-Acetylcysteine amide (NACA) to counteract oxidative stress, reduced pS129 -syn and -syn levels in USP14 deficient cells. Phospho-proteomic analyses revealed that USP14 is phosphorylated at S143 affecting its function and structure as shown by molecular modeling, and protein interaction studies. Re-expression of wild-type and the phospho-mimetic S143D-USP14 mutant decreased ROS, pS129 -syn, and -syn in USP14 lacking cells. These results demonstrate that pS129 -syn levels are sensitive to oxidative stress in SH-SY5Y dopaminergic cells. USP14 by stimulating the proteasome activity and reducing oxidative stress is a promising factor for targeting -syn and its pathogenic variants in PD.

neuroscience↗

bioRxiv2022

Post-vaccination Omicron infections induce broader immunity across antigenic space than prototype mRNA COVID-19 booster vaccination or primary infection

The rapid emergence of new SARS-CoV-2 variants challenges vaccination strategies. Here, we measured antigenic diversity among variants and interpreted neutralizing antibody responses following single and multiple exposures in longitudinal infection and vaccine cohorts. Antigenic cartography using primary infection antisera showed that BA.2, BA.4/BA.5, and BA.2.12.1 are distinct from BA.1 and closer to the Beta cluster. Three doses of an mRNA COVID-19 vaccine increased breadth to BA.1 more than to BA.4/BA.5 or BA.2.12.1. Omicron BA.1 post-vaccination infection elicited antibody landscapes characterized by broader immunity across antigenic space than three doses alone, although with less breadth than expected to BA.2.12.1 and BA.4/BA.5. Those with Omicron BA.1 infection after two or three vaccinations had similar neutralizing titer magnitude and antigenic breadth. Accounting for antigenic differences among variants of concern when interpreting neutralizing antibody titers aids understanding of complex patterns in humoral immunity and informs selection of future COVID-19 vaccine strains.

microbiology↗

bioRxiv2020

CDNF rescues motor neurons in three animal models of ALS by targeting ER stress

The role of chronic endoplasmic reticulum (ER) stress in the pathophysiology of Amyotrophic lateral sclerosis (ALS), as well as a potential drug target, has received increasing attention. Here, we investigated the mode of action and therapeutic effect of the ER resident protein cerebral dopamine neurotrophic factor (CDNF) in preclinical models of ALS harboring different genetic mutations. We identify that intracerebroventricular (i.c.v.) administration of CDNF significantly halts the progression of the disease and improves motor behavior in TDP43-M337V and SOD1-G93A rodent models of ALS. CDNF rescues motor neurons (MNs) in vitro and in vivo from ER stress associated cell death and its beneficial effect is independent of genetic disease etiology. Notably, CDNF regulates the unfolded protein response (UPR) initiated by transducers IRE1, PERK, and ATF6, thereby enhancing MN survival. Thus, CDNF holds great promise for the design of new rational treatments for ALS.

neuroscience↗

bioRxiv2017

Large-scale phenome-wide association study of PCSK9 loss-of-function variants demonstrates protection against ischemic stroke

PCSK9 inhibitors are a potent new therapy for hypercholesterolemia and have been shown to decrease risk of coronary heart disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large well-phenotyped biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes. We tested association of the PCSK9 loss-of-function variant rsll591147 (R46L) in a hypothesis-driven 11 phenotype set and a hypothesis-generating 278 phenotype set in 337,536 individuals of British ancestry in the United Kingdom Biobank (UKB), with independent discovery (n = 225K) and replication (n = 112K). In addition to the known association with lipid levels (OR 0.63) and coronary heart disease (OR 0.73), the T allele of rs11591147 showed a protective effect on ischemic stroke (OR 0.61, p = 0.002) but not hemorrhagic stroke in the hypothesis-driven screen. We did not observe an association with type 2 diabetes, cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. In the phenome-wide screen, the variant was associated with a reduction in metabolic disorders, ischemic heart disease, coronary artery bypass graft operations, percutaneous coronary interventions and history of angina. A single variant analysis of UKB data using TreeWAS, a Bayesian analysis framework to study genetic associations leveraging phenotype correlations, also showed evidence of association with cerebral infarction and vascular occlusion. This result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke, and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to low density lipoprotein cholesterol and atherosclerosis, suggesting that other effects are either small or absent.

genetics↗

bioRxiv2017

Bioimpedance and new onset heart failure: A longitudinal study of ~500,000 individuals from the general population

ImportanceHeart failure constitutes a high burden on patients and society, but although lifetime risk is high, it is difficult to predict without costly or invasive testing. Knowledge about novel risk factors could enable early diagnosis and possibly preemptive treatment.\n\nObjectiveTo establish new risk factors for heart failure.\n\nDesignWe applied supervised machine learning in UK Biobank in an agnostic search of risk factors for heart failure. Novel predictors were then subjected to several in-depth analyses, including multivariable Cox models of incident heart failure, and assessment of discrimination and calibration.\n\nSettingPopulation-based cohort study.\n\nParticipants500,451 individuals who volunteered to participate in the UK Biobank cohort study, excluding those with prevalent heart failure.\n\nExposure3646 variables reflecting different aspects of lifestyle, health and disease-related factors.\n\nMain OutcomeIncident heart failure hospitalization.\n\nResultsMachine learning confirmed many known and putative risk factors for heart failure, and identified several novel candidates. Mean reticulocyte volume appeared as one novel factor, and leg bioimpedance another; the latter appearing as the most important new factor. Leg bioimpedance was significantly lower in those who developed heart failure (p=1.1x10-72) during up to 9.8-year follow-up. When adjusting for known heart failure risk factors, leg bioimpedance was inversely related to heart failure (hazard ratio [95%CI], 0.60 [0.48-0.73]) and 0.75 [0.59-0.94], in age- and sex-adjusted and fully adjusted models, respectively, comparing the upper vs. lower quartile). A model including leg bioimpedance, age, sex, and self-reported history of myocardial infarction showed good predictive capacity of future heart failure hospitalization (C-index=0.82) and good calibration.\n\nConclusions and RelevanceLeg bioimpedance is inversely associated with heart failure incidence in the general population. A simple model of exclusively non-invasive measures, combining leg bioimpedance with history of myocardial infarction, age, and sex provides accurate predictive capacity.\n\nKey pointsO_ST_ABSQuestionC_ST_ABSWhich are the most important risk factors for incident heart failure?\n\nFindingsIn this population-based cohort study of ~500,000 individuals, machine learning identified well-established risk factors, but also several novel factors. Among the most important were leg bioimpedance and mean reticulocyte volume. There was a strong inverse relationship between leg bioimpedance and incident heart failure, also in adjusted analyses. A model entailing leg bioimpedance, age, sex, and self-reported history of myocardial infarction showed good predictive capacity of heart failure hospitalization and good calibration.\n\nMeaningLeg bioimpedance appears to be an important new factor associated with incident heart failure.

epidemiology↗