Inge Huitinga

Host: Inge Huitinga, i.huitinga@nin.knaw.nl

The Guest Speakers:
16.00 Antonio Luchicchi.
Antonio Luchicchi, PhD., Assistant Professor, Department of
Anatomy and Neurosciences, Amsterdam UMC, location VUmc.

Title: The dynamic of myelin blister formation in MS.

16.30 Aletta van den Bosch.
Department of Neuroimmunology, Netherlands
Institute for Neuroscience.

Title: Ultrastructural alterations in MS normal appearing white matter and implications for lesion formation.

Antonio Luchicchi Title: The dynamic of myelin blister formation in MS.

The cause of MS is still unknown. In this last decade an alternative hypothesis to explain the origin of MS has been postulated, according to which before the well-described autoimmune attack against the central nervous system myelin, a primary cytodegenerative process leads to myelin destabilization and disintegration. Recent observations from our lab have provided support to this hypothesis (named inside-out hypothesis of MS cause, as opposed to the more classic and prevalent outside-in hypothesis) showing that the normal appearing white matter (NAWM) in MS post-mortem brain material hosts an enhanced amount of typical local regions of myelin detachment from axonal processes (myelin blisters). Myelin blisters and other morphological alterations (i.e., axonal swellings) in MS are associated with specific biochemical and pathological fingerprints whose presence may be able to recapitulate the primary degenerative events that from seemingly normal axons lead to demyelination. Currently, we are investigating the dynamic of myelin blistering in the NAWM to understand the precise role of the pathological processes involved in primary myelin loss and secondary immune attack in MS human brains.

Aletta van den Bosch Title: Ultrastructural alterations in MS normal appearing white matter and implications for lesion formation.

During multiple sclerosis (MS), pathological progression continues to take place, however the underlying mechanisms remain unclear. Changes in the normal-appearing white matter (NAWM), specifically the axon-myelin unit, may predispose the tissue for lesion formation. Here, we systematically quantified ultrastructural and subcellular characteristics of the axonmyelin unit in MS NAWM and control white matter. Our data show less compact myelin composition, disorganization of the nodes of Ranvier and increased axonal mitochondria frequency in MS, which correlates with low-grade inflammation. We propose that these changes may trigger the formation of microglia nodules in the NAWM, which are observed throughout the disease course and are considered to represent the ‘earliest’ of MS lesions. By RNA sequencing of laser micro-dissected RNA nodules and immunohistochemistry, we found that specifically MS nodules reside in an inflammatory environment and express genes associated with lesion formation, lipid metabolism/catabolism and metabolic stress. Interestingly, MS but not stroke nodules had a tubular mitochondrial network, which may indicate hypermetabolism, perhaps due to the co-stimulation by myelin-derived oxidized phospholipids and pro-inflammatory cytokines provided by adjacent lymphocytes. Taken together, low-grade inflammation leading to decompaction of myelin in MS NAWM may trigger a cascade of events that can ultimately lead to an inflammatory MS lesion.