Mansoor, M. | Search bioRxiv

bioRxiv2026

Microglia drive demyelination via multiple sclerosis antibodies and BTK signaling

Microglia are the predominant immune cells in multiple sclerosis (MS) demyelinating lesions, where they phagocytose myelin, but whether they destroy myelin or merely scavenge its debris is unknown. Here, we explore whether pathogenic autoantibodies found in MS may induce the phagocytic destruction of myelin by microglia. Applying patient-derived, myelin-targeting antibodies to the mouse cortex, we developed an in vivo model of MS with focal demyelination that depended on epitope specificity and Fc gamma receptor and complement binding. Longitudinal monitoring of microglia-myelin interactions using in vivo two-photon microscopy revealed rapid microglial envelopment of intact myelin driving myelin loss, while single-cell RNA sequencing identified a demyelination-associated microglial signature. Parallel changes were observed in human MS lesions, where microglia enveloped intact myelin and similar genes were upregulated. Inhibition of Brutons tyrosine kinase (BTK) limited microglial transcriptional changes and prevented myelin loss following microglial envelopment. These findings directly implicate microglia in pathological myelin loss and support BTK inhibition as a therapeutic strategy to prevent demyelination by modulating microglia behavior.

neuroscience↗

bioRxiv2022

Poly ADP-Ribose Signaling is Dysregulated in Huntington Disease Patients

Huntington disease (HD) is a genetic neurodegenerative disease caused by CAG expansion in the Huntingtin (HTT) gene, translating to an expanded polyglutamine tract in the huntingtin (HTT) protein. Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Clinical studies show elevated DNA damage in HD, even at the premanifest stage. A major DNA repair node influencing neurodegenerative disease is the PARP pathway. Accumulation of poly ADP-ribose (PAR) has been implicated in Alzheimer and Parkinson diseases, as well as cerebellar ataxia. We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Human HD iPSC-derived neurons and patient- derived fibroblasts have diminished PAR response in the context of elevated DNA damage. We have defined a PAR-binding motif in huntingtin, detected huntingtin complexed with PARylated proteins in human cells during stress, and localized huntingtin to mitotic chromosomes upon inhibition of PAR degradation. Direct huntingtin PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy at the single molecule level. While wild type and mutant huntingtin did not differ in their PAR binding ability, purified wild type huntingtin protein increased in vitro PARP1 activity while mutant huntingtin did not. These results provide insight into an early molecular mechanism of HD, suggesting possible targets for the design of early preventive therapies. Significance statementA consensus on dysfunctional DNA repair has emerged in neurodegenerative disease research, with elevated poly ADP-ribose (PAR) signaling more recently implicated. In contrast, we have identified a deficient PAR response in Huntingtons disease (HD) patient spinal fluid samples and cells. This may be explained by the inability of huntingtin protein bearing the HD-causing mutation to stimulate production of PAR the way the wild type protein does. Since drugs that target PAR production and degradation have already been developed, these findings present an exciting avenue for therapeutic intervention for HD.

neuroscience↗