Studies on the Pathogenesis of Multiple Sclerosis

Abstract

The role of lysosomes in the pathogenesis of MS was studied by biochemical and ultrastructural techniques. Biochemical studies were performed on samples from 21 MS autopsies. The analyses included assays of acid proteinase, acid phosphatase, peptidase, neutral proteinase and esterase. The material for electron microscopy was obtained from ten biopsies made on MS patients during stereotaxic thalamotomy. In preliminary studies, the effect of autolysis on enzymatic activities was measured. These studies showed that acid hydrolases were stable enough to warrant further investigation. All enzyme activities studied were increased at the border zones of plaques, whereas in the macroscopically normal white matter only acid hydrolase activities were increased. Correspondingly, in electron microscopic studies, increased lysosomal response was found especially in astrocytes but also in oligodendrocytes. In astrocytes the number of heterolysosomes was conspicously increased and they were seen both in the perikaryon and in the cell processes. Such lysosomes often contained myelin-like membrane material. The presence of foreign phagocytizing cells could not be demonstrated except around the blood vessels. Furthermore, it appeared that myelin layers were not phagocytized by direct peeling process. These studies, suggest that early lysosomal changes occur in MS white matter and that such changes are mainly due to the phagocytosis of myelin inside astrocyte lysosomes. The possibility that the astrocyte response is a secondary phenomenon, which is preceded by other myelin destroying mechanisms is discussed.

Lysosomes as a therapeutic target

“…In MS, studies conducted on white matter demon strated that lysosomes are involved in myelin sheath degeneration as well as in the fragmented protein forma tion. Lysosomal swelling was observed near the degen erated materials of astrocytes 146 , and an accumulation of lipids was found 60 . It has been hypothesized that lyso somal swelling/permeabilization might cause the release of hydrolases in the cytosol, where they affect native proteins 147 .…”

Degradation of basic protein in myelin by neutral proteases secreted by stimulated macrophages: A possible mechanism of inflammatory demyelination

“…However, the mechanism by which the inflammatory cells, predominantly macrophages and lymphocytes in MS and EAE, participate in the process of demyelination has not yet been defined. Most attention has been directed toward acid proteases and lysosomal hydrolases which increase in and around MS plaques (3)(4)(5)(6)(7)(8)(9) and in lesions in animals with EAE (10)(11)(12)(13)(14)(15). It has…”

Critical evaluation of the postmortem factors influencing neurochemical analyses of brain autopsies

“…AChE has been reported to resist postmortem delay relatively well in the human brain tissue (Himwich et al 1961, Rime et al 1973, McGeer & McGeer 1976. The situation was the same in the present study although the length of the deep-frozen storage time correlated negatively with the A C E activity, but the storage time was also long.…”

“…Acetylcholinesterase (AChE) activity is known to decrease in rat brain after death (Fahn & Cote 1976). In the human brain the situation for some unknown reason seems to be different (Himwich et al 1961, Rime et al 1973. AChE remains about the same level.…”