Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signaling, but its triggers, targets, and disease relevance are not clear. Using site-selective suppressors and genetic manipulations together with mitochondrial ROS imaging and multiomic profiling, we found that CIII is the dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli.
View Article and Find Full Text PDFAstrocytic receptors influence cognitive function and can promote behavioral deficits in disease. These effects may vary based on variables such as biological sex, but it is not known if the effects of astrocytic receptors are dependent on sex. We leveraged in vivo gene editing and chemogenetics to examine the roles of astrocytic receptors in spatial memory and other processes.
View Article and Find Full Text PDFObjective: The objective of this study was to examine measurement properties of the Joint replacement version for Hip Disability and Osteoarthritis Outcome Score (HOOS-JR) using Rasch analysis in patients with osteoarthritis of hip (HOA).
Design: Cross-sectional clinical measurement SETTING: Patient outcomes database at a tertiary care hospital PARTICIPANTS: Convenience sampling of patients with HOA scheduled for total hip arthroplasty (N=327) OUTCOME MEASURES AND ANALYSIS: The data for pre-surgery assessments for patients with HOA were extracted from an existing database. Variables extracted included HOOS-JR scores, demographic information (age, sex), health-related data, and anthropometric variables.
Transactivating response region DNA binding protein 43 (TDP-43) pathology is prevalent in dementia, but the cell type-specific effects of TDP-43 pathology are not clear, and therapeutic strategies to alleviate TDP-43-linked cognitive decline are lacking. We found that patients with Alzheimer's disease or frontotemporal dementia have aberrant TDP-43 accumulation in hippocampal astrocytes. In mouse models, induction of widespread or hippocampus-targeted accumulation in astrocytic TDP-43 caused progressive memory loss and localized changes in antiviral gene expression.
View Article and Find Full Text PDFIdentifying neurobiological mechanisms of aging-related parkinsonism, and lifestyle interventions that mitigate them, remain critical knowledge gaps. No aging study, from rodent to human, has reported loss of any dopamine (DA) signaling marker near the magnitude associated with onset of parkinsonian signs in Parkinson's disease (PD). However, in substantia nigra (SN), similar loss of DA signaling markers in PD or aging coincide with parkinsonian signs.
View Article and Find Full Text PDFToxicant resistance is a complex trait, affected both by genetics and the environment. Like most complex traits, it can exhibit sexual dimorphism, yet sex is often overlooked as a factor in studies of toxicant resistance. Paraquat, one such toxicant, is a commonly used herbicide and is known to produce mitochondrial oxidative stress, decrease dopaminergic neurons and dopamine (DA) levels, and decrease motor ability.
View Article and Find Full Text PDFThe limitations of classical drugs have spurred the development of covalently tethered photoswitchable ligands to control neuromodulatory receptors. However, a major shortcoming of tethered photopharmacology is the inability to obtain optical control with an efficacy comparable with that of the native ligand. To overcome this, we developed a family of branched photoswitchable compounds to target metabotropic glutamate receptors (mGluRs).
View Article and Find Full Text PDFMutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10), a mitochondrial protein of unknown function, cause a disease spectrum with clinical features of motor neuron disease, dementia, myopathy and cardiomyopathy. To investigate the pathogenic mechanisms of CHCHD10, we generated mutant knock-in mice harboring the mouse-equivalent of a disease-associated human S59L mutation, S55L in the endogenous mouse gene. CHCHD10 mice develop progressive motor deficits, myopathy, cardiomyopathy and accelerated mortality.
View Article and Find Full Text PDFBackground: The serotonergic system is a well-established modulator of l-dopa-induced dyskinesia. To date, targeting serotonin transporters or serotonin receptor subtype 1A (5-HT ) reduces l-dopa-induced dyskinesia in animal models; however, these strategies have failed to translate clinically. Ideally, a compound acting at both known antidyskinetic sites could optimize serotonin-mediated approaches.
View Article and Find Full Text PDFIndividually, D1 and D3 dopamine receptors (DR and DR, respectively) have been implicated in L-DOPA-induced dyskinesia (LID). Of late, direct DR-DR interactions have been linked to LID yet remain enigmatic. Therefore, the current research sought to characterize consequences of putative DR-DR interactions in dyskinesia expression and in LID-associated downstream cellular signaling.
View Article and Find Full Text PDFBackground And Purpose: Symptoms of Parkinson's disease are commonly managed using selective dopamine D receptor agonists, including ropinirole. While D agonists are useful in early-stage Parkinson's disease, they tend to lose efficacy in later disease stages and do not appear to modify disease progression. We have recently developed a novel 'multifunctional' compound, D-512: a high-affinity D receptor agonist with antioxidant and other neuroprotective properties that may limit Parkinson's disease progression.
View Article and Find Full Text PDFBackground: Increased extracellular glutamate may contribute to l-dopa induced dyskinesia, a debilitating side effect faced by Parkinson's disease patients 5 to 10 years after l-dopa treatment. Therapeutic strategies targeting postsynaptic glutamate receptors to mitigate dyskinesia may have limited success because of significant side effects. Increasing glutamate uptake may be another approach to attenuate excess glutamatergic neurotransmission to mitigate dyskinesia severity or prolong the time prior to onset.
View Article and Find Full Text PDFl-DOPA remains the benchmark treatment for Parkinson's disease (PD) motor symptoms, but chronic use leads to l-DOPA-induced dyskinesia (LID). The serotonin (5-HT) system has been established as a key modulator of LID and 5-HT receptors (5-HTR) stimulation has been shown to convey anti-dyskinetic effects. However, 5-HTR agonists often compromise clinical efficacy or display intrinsic side effects and their site(s) of actions remain debatable.
View Article and Find Full Text PDFl-DOPA is the standard treatment for Parkinson's disease (PD), but chronic treatment typically leads to abnormal involuntary movement or dyskinesia (LID) development. Although poorly understood, dyskinetic mechanisms involve a complex interaction between the remaining dopamine system and the semi-homologous serotonin and norepinephrine systems. Serotonin and norepinephrine transporters (SERT and NET, respectively) have affinity for dopamine uptake especially when dopamine transporters (DAT) are scant.
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