Project Summary/Abstract:
Acute optic neuritis (ON) is often the initial presenting manifestation of autoimmune
demyelinating disorders such as Multiple Sclerosis (MS). Good recovery of vision after ON is common,
but a considerable number of MS patients experience poor outcomes with severe visual impairment
and permanent blindness as disease progresses. The increasing prevalence of MS will cause an
immense social and financial challenge for health care systems and more studies are needed to
improve treatment success in these diseases.
Impaired recycling of cholesterol-rich myelin debris and decreased de novo synthesis of
cholesterol have been identified as key limiting factors of recovery in demyelinating animal models. We
have demonstrated decreased expression of the main cholesterol efflux transporter1, Abca1, and
altered cholesterol homeostasis in the retinogeniculate system of animals with Experimental
Autoimmune Encephalomyelitis (EAE)-ON. However, the exact mechanism by which changes in Abca1
expression affect cholesterol recycling remain elusive. We hypothesize that this impairment in
cholesterol synthesis and transport significantly affects RGC survival, integrity of synaptic plasticity and
remyelination and that restoration of cholesterol homeostasis via Abca1 regulatory feedback
ameliorates visual impairment.
In specific aim 1, we will determine the regulatory influence of ABCA1 expression on sterol
synthesis and synaptic plasticity, cholesterol transport, and myelination in vitro. Eye and brain
organoids from healthy subjects and MS patients will be exposed to Abca1 inhibitors, TNFa/IFN¿, or
the demyelinating agent Lysolecithin. Effects of rescued Abca1 expression on sterol synthesis,
cholesterol uptake and transport, synaptogenesis and myelination will be examined using single-cell
RNA-sequencing, immunohistochemistry, and cholesterol efflux assays. In specific aim 2, we will
determine the molecular, functional, and structural impact of Abca1 expression changes in the
retinogeniculate pathway of EAE-ON and MS. EAE-ON will be induced in mice and effects of Abca1
expression changes will be determined using optokinetic response, optical coherence tomography,
pattern electroretinography, and visual evoked potentials, followed by postmortem molecular and
histopathologic analysis. Also, disruption in cholesterol homeostasis will be determined in MS donor
eye tissue.
Our proposed experiments will significantly advance the understanding of the role of cholesterol
homeostasis in MS-like ON and provide an invaluable resource for future translational and therapeutic
studies.