Activation of the unfolded protein response in multiple sclerosis: Relevance for lesion development and progression

• Applicant: Professor Dr. Markus Kipp
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Nuclear Medicine, Radiotherapy, Radiobiology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398138584

The primary functions of oligodendrocytes are to produce the myelin sheath, which hastens the conduction of action potential and protects axons from inflammatory environments, and to provide nutritional support to axons. The death of oligodendrocytes and the subsequent demyelination and axonal degeneration are hallmarks of multiple sclerosis (MS). What kills the oligodendrocytes and to what extent this is linked to axonal degeneration are not well understood, especially during progressive MS. The unfolded protein response (UPR) represents a signaling pathway well known for restoring cellular homeostasis. Although UPR activation can aid cells in adapting to stress, it can also trigger apoptosis. However, it is not known how the UPR selects between cytoprotective and proapoptotic outputs. Such mechanisms may regulate oligodendrocyte pathology and, in consequence, neurodegeneration, especially during the progressive stage of MS, which is currently refractory to any therapy. There is accumulating evidence that inflammatory mediators as well as metabolic disturbances also activate the UPR, which was originally described as triggered by misfolded proteins. Not surprisingly, UPR activation was reported in several cell types in MS lesions, including oligodendrocytes. Of note, oligodendrocytes are highly sensitive to activation of the UPR, which has unique features in these cells. We will first phenotype the UPR signatures in different MS animal models and compare them to the signature from human MS samples. We will utilize noninflammatory (cuprizone) and T cell-dominated experimental autoimmune encephalomyelitis (EAE) models (MOG-EAE) of MS, which are suited for studying individual and defined pathogenetic mechanisms (i.e., metabolic- versus immune-mediated oligodendrocyte degeneration). Second, we will focus on the functional role of the UPR transcription factor DNA damage-inducible transcript 3 (DDIT3). Our preliminary results show that DDIT3 is specifically expressed by oligodendrocytes in a progressive MS model, and oligodendrocytes in Ddit3-deficient mice are protected from apoptosis. This study aims to understand how inflammation, UPR activation, oligodendrocyte loss, and axonal pathology are linked. We will complement standard methods with design-based stereology for quantifying oligodendrocyte preservation. To further understand the complex signaling cascade linking UPR activation with oligodendrocyte death, we will perform mechanistic studies using primary oligodendrocyte cultures and suitable cell lines. The knowledge gained from these studies will provide a foundation for developing therapeutic strategies that protect oligodendrocytes and neurons in progressive MS.

• DFG Programme: Research Grants