Samantha M. Meadows

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. Astrocytic CIII-ROS production was dependent on nuclear factor-κB (NF-κB) and the mitochondrial sodium-calcium exchanger (NCLX) and caused oxidation of select cysteines within immune and metabolism-associated proteins linked to neurological disease. CIII-ROS amplified metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitated neuronal toxicity in a non-cell- autonomous manner. As proof-of-concept, suppression of CIII-ROS in mice decreased dementia-linked tauopathy and neuroimmune cascades and extended lifespan. Our findings establish CIII-ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease.

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. These changes were cell-autonomous and correlated with impaired astrocytic defense against infectious viruses. Among the changes, astrocytes had elevated levels of interferon-inducible chemokines, and neurons had elevated levels of the corresponding chemokine receptor CXCR3 in presynaptic terminals. CXCR3 stimulation altered presynaptic function and promoted neuronal hyperexcitability, akin to the effects of astrocytic TDP-43 dysregulation, and blockade of CXCR3 reduced this activity. Ablation of CXCR3 also prevented TDP-43–linked memory loss. Thus, astrocytic TDP-43 dysfunction contributes to cognitive impairment through aberrant chemokine-mediated astrocytic-neuronal interactions.

Cognitive processes and neurocognitive disorders are regulated by astrocytes and have prominent sex differences. However, the contribution of astrocytes to sex differences is not known. We leveraged astrocyte-targeted gene editing and chemogenetics in adult mice to reveal that astrocytic glutamate receptors and other G protein-coupled receptors (GPCRs) modulate hippocampus-dependent cognitive function in a sexually dimorphic manner. In females, spatial memory was improved by increasing metabotropic glutamate receptor 3 (mGluR3) in astrocytes or stimulating astrocytic G _i/o -coupled signaling, whereas stimulating G _s -coupled signaling impaired memory. However, in males, memory was improved by reducing mGluR3 or stimulating G _s -coupled signaling, whereas stimulating G _i/o -coupled signaling impaired memory. Thus, memory requires a sex-specific balance of astrocytic G _s -coupled and G _i/o -coupled receptor activities, and disease-associated alterations or therapeutic targeting of these pathways may cause opposing sex-dependent effects on cognitive function. Summary: Glia cause sex-specific changes in cognition

TDP-43 pathology is prevalent in dementia but the cell type-specific effects of TDP-43 are not clear and therapeutic strategies to alleviate TDP-43-linked cognitive decline are lacking. We found that patients with Alzheimer’s disease (AD) or frontotemporal dementia (FTD) 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. These changes were cell-autonomous and correlated with impaired astrocytic defense against infectious viruses. Among the changes, astrocytes had elevated levels of interferon-inducible chemokines and neurons had elevated levels of the corresponding chemokine receptor CXCR3 in presynaptic terminals. CXCR3 stimulation altered presynaptic function and promoted neuronal hyperexcitability, akin to the effects of astrocytic TDP-43, and blockade of CXCR3 reduced this activity. Ablation of CXCR3 also prevented TDP-43-linked memory loss. Thus, astrocytic TDP-43 dysfunction contributes to cognitive impairment through aberrant chemokine-mediated astrocytic-neuronal interactions. Summary: In dementia, protein buildup in glia enhances chemokine signaling to synapses and impairs specific aspects of neurocognitive function.

Mutations 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^S55L mice develop progressive motor deficits, myopathy, cardiomyopathy and accelerated mortality. Critically, CHCHD10 accumulates in aggregates with its paralog CHCHD2 specifically in affected tissues of CHCHD10^S55L mice, leading to aberrant organelle morphology and function. Aggregates induce a potent mitochondrial integrated stress response (mtISR) through mTORC1 activation, with elevation of stress-induced transcription factors, secretion of myokines, upregulated serine and one-carbon metabolism, and downregulation of respiratory chain enzymes. Conversely, CHCHD10 ablation does not induce disease pathology or activate the mtISR, indicating that CHCHD10^S55L-dependent disease pathology is not caused by loss-of-function. Overall, CHCHD10^S55L mice recapitulate crucial aspects of human disease and reveal a novel toxic gain-of-function mechanism through maladaptive mtISR and metabolic dysregulation.

Background: 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_1A) 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. Vilazodone is a selective serotonin reuptake inhibitor and a partial 5‐HT_1A agonist approved by the U.S. Food and Drug Administration, situating Vilazodone in a unique position to reduce l‐dopa‐induced dyskinesia without compromising l‐dopa‐mediated motor improvements. Objectives: The goal of the present study was to characterize Vilazodone's effects on l‐dopa‐induced behaviors, neurochemistry and gene expression in unilateral 6‐hydroxydopamine‐lesioned hemi‐parkinsonian rats. Methods: In experiments 1 and 2, l‐dopa‐naïve and l‐dopa‐primed animals were coadministered Vilazodone and l‐dopa daily for 3 weeks to model subchronic use, and behavioral, neurochemical, and messenger RNA (mRNA) expression changes were measured. In experiment 3, dyskinetic behavior was assessed following 5‐HT_1A or serotonin receptor subtype 1B blockade prior to Vilazodone–l‐dopa coadministration. Results: Vilazodone significantly suppressed developing and established l‐dopa‐induced dyskinesia without compromising the promotor effects of l‐dopa therapy. In the dopamine‐depleted striatum, Vilazodone–l‐dopa cotreatment increased dopamine content, suggesting a normalization of dopamine kinetics in dyskinetic brain, and reduced l‐dopa‐induced c‐Fos and preprodynorphin mRNA overexpression, indicative of attenuated dopamine D₁ receptor‐mediated direct pathway overactivity. Only 5‐HT_1A antagonism partially attenuated Vilazodone's antidyskinetic efficacy, suggesting both serotonin transporter‐dependent effects and 5‐HT_1A receptors in Vilazodone's actions. Conclusions: Our findings show Vilazodone has a serotonin‐dependent effect on rodent l‐dopa‐induced dyskinesia and implicate the potential for repositioning Vilazodone against l‐dopa‐induced dyskinesia development and expression in Parkinson's disease patients. © 2018 International Parkinson and Movement Disorder Society

Background and Purpose: Symptoms of Parkinson's disease are commonly managed using selective dopamine D_2/3 receptor agonists, including ropinirole. While D_2/3 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_2/3 receptor agonist with antioxidant and other neuroprotective properties that may limit Parkinson's disease progression. This study sought to compare the anti‐Parkinsonian properties of the clinically used compound, ropinirole, with those of the novel compound, D‐512.Experimental Approach: A rat model of Parkinson's disease was created by unilaterally infusing 6‐hydroxydopamine, a dopamine neurotoxin, into the medial forebrain bundle. D‐512 was compared with ropinirole for ability to stimulate spontaneous motor activity and reverse Parkinsonian akinesia. These beneficial effects were compared against each drug's liability to provoke dyskinesia, a common motor side effect.Key Results: Both compounds increased spontaneous movement, but D‐512 showed a longer duration of action. Only D‐512 was able to significantly reverse forelimb akinesia. Drug‐induced dyskinesia was similar for equivalent doses.Conclusions and Implications: Compared with ropinirole, D‐512 showed greater peak‐dose efficacy and a longer duration of action, despite a similar side‐effect profile. Our results add to earlier data showing that D‐512 is superior to available D_2/3 agonists and could merit clinical investigation.