Ali Moshaymesh
Research Mentor(s): Sebastian Werneburg
Mentor Department: Ophthalmology and Visual Sciences
Authors: Ali Moshaymesh, Gabrille Mey, Sebastian Werneburg
Session: Session 7 (4:00pm – 4: 50pm)
Presentation Type: Oral
Abstract
Multiple Sclerosis (MS) is a neurodegenerative demyelinating disease of the central nervous system (CNS). While disease-modifying therapies that manage acute symptoms exist, there is no treatment halting the progressive degeneration of neural circuits. This highlights the urgent unmet clinical need to better understand the molecular mechanisms underlying degenerative pathology. Using the visual circuit as a model, one of the most frequently affected circuits in MS, our lab identified a pronounced loss of synapses in the visual thalamus, which leads to neural connectivity disruptions and functional impairment. Notably, circuit disruption was caused by the CNS immune cells, microglia, which exhibited a reactive phenotype. Using the cuprizone model of demyelination, one of the most widely used MS models, we have found compelling new evidence identifying the induction of the integrated stress response (ISR) in reactive microglia at peak stages of demyelination. The ISR is a cytoprotective pathway that cells utilize in stress and inflammatory conditions and is activated in demyelinated lesions of postmortem MS brains. ISR inhibition has also been shown to alter microglia reactivity in neuroinflammation, but if the ISR affects microglial reactivity in demyelinating disease remains unexplored. To test this, our ongoing work interrogates the induction of the ISR at multiple early stages of cuprizone treatment and aims to manipulate ISR induction specifically in microglia using cell-specific genetic mouse models. Together, this work will allow us to better assess ISR’s involvement in microglial reactivity and potentially portray the ISR in microglia as a promising new target for treatment, providing an approach that aims to treat microglia-mediated disruption of neural circuits.
