Autoimmunity to a ribonucleoprotein drives neuron loss in multiple sclerosis models

Area of Science:

• Neuroimmunology
• Neurobiology
• Molecular Medicine

Background:

• Neurodegeneration causes permanent disability in multiple sclerosis (MS).
• Autoimmunity to intraneuronal RNA binding proteins, like heterogenous nuclear ribonucleoprotein A1 (hnRNP A1), is implicated in MS neurodegeneration.
• Previous studies suggested anti-hnRNP A1 antibodies worsen experimental autoimmune encephalomyelitis (EAE) but did not clarify causality.

Purpose of the Study:

• To investigate the temporal relationship between anti-hnRNP A1 antibody-mediated hnRNP A1 dysfunction and neurodegeneration.
• To elucidate the mechanism of antibody-induced neurodegeneration in MS models.

Main Methods:

• Utilized in vivo and in vitro models of anti-hnRNP A1 antibody-mediated autoimmunity.
• Analyzed hnRNP A1 dysfunction markers (mislocalization, stress granule formation) and neurodegeneration markers (necroptosis, cell death) over time.
• Investigated the role of necroptosis inhibition and clathrin-mediated endocytosis in the disease process.

Main Results:

• Anti-hnRNP A1 antibody treatment led to hnRNP A1 mislocalization, nuclear depletion, altered RNA expression, and stress granule formation.
• This was followed by increased necroptotic signaling and neuronal cell death.
• Inhibition of necroptosis partially rescued neurodegeneration, and clathrin knockdown reduced antibody uptake into neurons.

Conclusions:

• Identified a novel antibody-mediated mechanism driving neurodegeneration in MS.
• Demonstrated that anti-hnRNP A1 antibody-induced hnRNP A1 dysfunction precedes and causes neurodegeneration.
• Suggests targeting this pathway, including necroptosis and antibody uptake, may prevent irreversible neurological damage in MS.