Biology subjects

Yednock, T.

Publications and source records attributed to Yednock, T..

3 recordsLinked to original sources

bioRxiv2021

Microglia Mediate Early Corticostriatal Synapse Loss and Cognitive Dysfunction in Huntingtons Disease Through Complement-Dependent Mechanisms

Huntingtons disease (HD) is a devastating monogenic neurodegenerative disease characterized by early, selective pathology in the basal ganglia despite the ubiquitous expression of mutant huntingtin. The molecular mechanisms underlying this region-specific neuronal degeneration and how these relate to the development of early cognitive phenotypes are poorly understood. Here, we show that there is selective loss of synaptic connections between the cortex and striatum in postmortem tissue from HD patients that is associated with the increased activation and localization of complement proteins, innate immune molecules, to markers of these synaptic elements. We also find that levels of these secreted innate immune molecules are elevated in the CSF of premanifest HD patients and correlate with established measures of disease burden. In preclinical genetic models of HD we show that complement proteins mediate the selective elimination of corticostriatal synapses at an early stage in disease pathogenesis marking them for removal by microglia, the brains resident macrophage population. This process requires mutant huntingtin to be expressed in both cortical and striatal neurons and inhibition of this complement-dependent elimination mechanism through administration of a therapeutically relevant C1q function blocking antibody or genetic ablation of a complement receptor on microglia, prevented synapse loss, increased excitatory input to the striatum and rescued the early development of visual discrimination learning and cognitive flexibility deficits in these models. Together, our findings implicate microglia and the complement cascade in the selective, early degeneration of corticostriatal synapses and the development of cognitive deficits in presymptomatic HD, and also provide new preclinical data to support complement as a therapeutic target for early intervention.

neuroscience↗

bioRxiv2020

Complement factor C1q mediates chronic neuron loss and inflammation post-brain injury

While traumatic brain injury (TBI) acutely disrupts the cortex, most TBI-related disabilities reflect secondary injuries that accrue over time. The thalamus is a likely site of secondary damage because of its reciprocal connections with the cortex. Using a mouse model of cortical injury that does not directly damage subcortical structures, we found a chronic increase in C1q expression specifically in the corticothalamic circuit. Increased C1q expression co-localized with neuron loss and chronic inflammation, and correlated with altered cortical rhythms. Blocking C1q counteracted most of these outcomes, suggesting that C1q is a disease modifier in TBI. Since the corticothalamic circuit is important for sensory processing, attention, cognition, and sleep, all of which can be impaired by TBI, this circuit could be a new target for treating TBI-related disabilities.

neuroscience↗

bioRxiv2019

Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of α-Synuclein Protect Against Diverse α-Synuclein Mediated Dysfunctions

The over-expression and aggregation of -synuclein (Syn) are linked to the onset and pathology of Parkinsons disease. Native monomeric Syn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of Syn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes. Using a surface plasmon resonance high-throughput screen, in which monomeric Syn is incubated with microchips arrayed with tethered compounds, we identified novel Syn interacting drug-like compounds. Because these small molecules could impact a variety of Syn forms present in the ensemble, we tested representative hits for impact on multiple Syn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits Syn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by Syn overexpression, and a compound blocking cellular transmission of Syn. Our studies demonstrate that drug-like small molecules that interact with native Syn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of Syn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinsons disease.

neuroscience↗