Dissertation

Categorització dels cossos de poliglucosà cerebrals basada en la presència de neoepítops reconeguts per IgMs naturals

Augé Marí, Elisabet

2018

Overview

The term polyglucosan bodies (PGBs) refers to complex aggregates composed of relatively large glucose polymers reaching diameters of tens of micrometres. PGBs have been reported in the central nervous system, but also in other organs and tissues, such as heart, skeletal muscle and liver. These aggregates have been described in humans and other species and they have been most widely studied in mammals. Different forms of PGBs have been related to particular situations or specific diseases. During the ageing process, human brain accumulates one type of PGBs called corpora amylacea (CA). Although CA have been studied for several years, their origin and function remain unclear. PGBs are also associated with Lafora disease, a neurodegenerative disorder that is characterized by the presence of PGBs structures called Lafora bodies (LBs). On the other hand, brain ageing in mice leads to the progressive appearance and expansion of degenerative granular PGBs frequently referred to as Periodic Acid Schiff (PAS) granules. These granules, which are present mainly in the hippocampus, originate in astrocytes processes and tend to appear in clusters. Each cluster corresponds to the set of granules of a determined astrocyte. Recently, our research group have reported the presence of neo-epitopes recognized by IgMs on these structures. These IgMs, which are present as contaminants in many commercial antibodies, are responsible of numerous false positive staining on these bodies when immunohistochemical procedures are used.This thesis aimed to study the origin, composition and function of PGBs that appear with age and in neurodegenerative conditions such as Alzheimer’s disease and Lafora disease.The results show that CA are similar structures to PAS granules from mice brain and that CA also contain neo-epitopes. In both cases, the neo-epitopes can be recognized by natural IgM antibodies, suggesting a new relation between PGBs and the natural immune system. Moreover, the false staining produced by the natural IgMs that bind to the neoepitopes clarified some controversial results previously described about the presence of some components on CA and their function. We also determined that CA accumulate non-degradable products generated during ageing process and increased in neurodegenerative condictiones, such as Alzheimer’s disease. Taking all into account, we hypothesize that CA are waste containers in which deleterious or residual products are isolated to be later eliminated through the action of the innate immune system. On the other hand, we observed that malin deficient mice, a mouse model of Lafora disease, present high amounts of two distinct types of PGBs: PAS granules or CA-like granules, originated in astrocytes and containing neo-epitopes, and neuronal LBs, which are exclusive of Lafora disease and do not contain neo-epitopes. Thus, the absence of malin triggers the formation of PGBs in neurons but also enhances their development in astrocytes. We postulate that, against to the current believe, astrocytes are involved in the etiopathogenesis of Lafora disease.Overall results show that the distinct PGBs have been studied until now with a specific and limited perspective. A global or main picture is necessary to obtain the knowledgement of their significance.

• Publisher: ProQuest Dissertations & Theses
• Subject: Biochemistry / Immunology / Neurosciences
• ISBN: 9798314827901