Vergleichende Untersuchungen über die Pathogenese von Axonschäden und Remyelinisierung bei Enzephalitiden sowie genetischen Defekten des zentralen Nervensystems
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- Tierärztliche Hochschule
- Demyelinating diseases of the central nervous system are an etiologically heterogeneous group; in which a primary loss of myelin is accompanied by preservation of the axonal integrity. In the last years; there was a paradigm shift in multiple sclerosis in humans as well as in its animal models like canine distemper virus (CDV) infection. Nevertheless; the pathogenesis of axonopathies and the influence of several cellular and acellular factors on axonal growth promoting or inhibitory properties were not investigated so far. Additionally; in diseases with neurological deficits and a suspected genetic mutation as a possible cause a detailed characterization on a molecular and morphological level is often missing. New therapeutical strategies in demyelinating diseases include potentially remyelinating aldynoglial cells; also known as central Schwann cells. In the introduction; an overview concerning the structure of axons; axonal transport; relevance of axonopathies in inflammatory and degenerative diseases of the central nervous system (CNS) is given followed by a description of the neurotrophin receptor p75NTR and its expression in several differentiation stages in Schwann cells. The influence of remyelinating Schwann cells as a regenerative process on neurodegenerative processes is briefly described. In addition; the canine and murine diseases (canine distemper virus infection; granulomatous meningoencephalitis [GME]; neuroaxonal dystrophy [NAD]; Theiler`s murine encephalomyelitis [TME] and dystonia musculorum) investigated in this habilitation were delineated. The aim was the comparative contemplation of different naturally occurring and experimentally induced CNS diseases using several in situ and in vitro methods. The ten publications summarized in this thesis can be allocated to six aims: 1. Characterization of the pathogenesis of axonal damage in CDV-induced demyelinating leukoencephalitis 2. Characterization of changes in the quality and quantity of extracellular matrix in CDV-induced demyelinating leukoencephalitis 3. Description and characterization of p75NTR-positive Schwann cells in the brain of dogs with CDV-induced demyelinating leukoencephalitis and GME 4. Characterization of neurodegenerative changes in a new variant of NAD based on a mutation in the canine tectonin beta-propeller repeat-containing protein 2 (TECPR2) gene 5. Characterization of the pathogenesis of axonopathies in TME 6. Characterization of neurodegenerative changes in a new variant of murine dystonia musculorum In canine distemper demyelinating leukoencephalitis; an increased immunoreactivity of non-phosphorylated neurofilament; a marker for damaged axons; was accompanied by loss of cytoskeletal and motor proteins. In contrast to the results on the protein level; transcriptional upregulation of genes; which code for neurofilament subunits and motor proteins; was detected in chronic lesions compared to subacute lesions. Immunohistochemically; hints for regeneration were obvious; consisting of axonal immunoreactivity for HIF1α. Nevertheless; GAP-43; erythropoietin and its receptor showed no regulation or were downregulated. The extracellular matrix (ECM) is regarded as a mainly axonal growth inhibitory factor. In CDV-infected dogs; changes in the quality and quantity of the ECM were detected compared to controls. Aggrecan expression was upregulated in early and late lesions; whereas the expression of collagen type I and IV as well as fibronectin was upregulated mainly in late lesions. In contrast; expression of phosphacan was downregulated in early and late lesions compared to controls. Transcriptome analysis showed an upregulation of ECM modulating enzymes. Summarized; changes in the composition and quantity represent mainly posttranscriptional events especially in late CDV lesions. The accumulated ECM is supposed to restrain regenerative processes in canine distemper encephalitis. p75NTR-positive Schwann cells were detected in CDV-induced lesions as well as in canine granulomatous meningoencephalitis. However; in few late CDV lesions only single P0- and periaxin-positive cells; which are indicative of Schwann cell remyelination; could be detected. In GME; approximately two thirds of p75NTR-positive cells coexpressed the transcriptional factor SOX2. About one third of the GME lesions showed periaxin- and P0-positive cells; interpreted as Schwann cell myelination. Additionally; lesions in the brainstem without p75NTR-positive Schwann cells showed a significantly higher number of damaged axons compared to lesions with p75NTR- or p75NTR-/periaxin-positive cells. In conclusion; p75NTR-/SOX2-positive cells in GME lesions could be interpreted as an early regenerative process. In CDV infection; the early axonal damage may represent a triggering factor for the differentiation of p75NTR expressing Schwann cells. Nevertheless; in contrast to GME; p75NTR-positive cells remain in an immature premyelinating state. A juvenile-onset form of NAD in the Spanish waterdog is in a causal relationship with a mutation in the canine tectonin beta-propeller repeat-containing protein 2 (TECPR2) gene. Morphologically; the disease is characterized by neuronal degeneration in the grey matter of cerebrum and cerebellum as well as in some nuclei in the brainstem; respectively. Additionally; a neuronal loss and spheroid formation were detectable in sensory nuclei and nerve tracts of the spinal cord. Spheroids showed an accumulation of autophagosomes; so that pathogenetically a disturbance of the autophagy process was supposed. In experimental TMEV infection; susceptible SJL/J mice showed axonal damage early in the course of the disease. Axonopathies occurred before demyelination which verified the hypothesis of the inside-out model of primary axonal damage with secondary demyelination as a result of viral infection. These changes were mirrored not only at the protein level but also in the transcriptome analysis. In TMEV-infected mice; downregulation of nicotinamide-adenine-dinucleotide synthesizing enzymes NMAT1 and NMAT2 and upregulation of nicotinamide-adenine-dinucleotide metabolizing enzyme PARP1 point towards an axonal self-destructive program as a consequence of nicotinamide-adenine-dinucleotide depletion. In cerebrum and cerebellum; susceptible SJL/J mice showed significantly more axonale damage and a decreased axonal density after TMEV infection compared to non-susceptible C57BL/6 mice. A new spontaneous mutation in the dystonin gene of C57BL/6N mice; which causes the disease dystonia musculorum; caused complete loss of dystonin protein in multiple organ systems including the central nervous system in homozygous mice. Histopathological changes consisted of axonal damage and other neurodegenerative findings which could be found mainly in sensory nuclei in the brainstem and few motor neurons. Pathogenetically; a primary axonopathy with secondary degenerative changes in the neuronal soma in terms of a dying back phenomenon was supposed. The comprehensive discussion of this thesis was composed of a systematic comparison of the extent of axonopathies and differences in the pathogenesis in different diseases (distemper; TME; NAD and dystonia musculorum; respectively). Additionally; disparities in the differentiation of potentially remyelinating Schwann cells in canine distemper encephalitis and GME were detected. Consecutively; axonopathies do not comprise stereotype procedures but exhibit differences in location; temporal distribution and affected substructures concerning investigated diseases in this thesis. Therefore; many intervention strategies in prevention and therapy of neurodegenerative diseases can be established in further studies. In GME; Schwann cells showed a phenotype similar to the peripheral nervous system. Consequently; a dedifferentiation; an infiltration of Schwann cells from the periphery and a redifferentiation of glial precursor cells are possible regenerative mechanisms for neurodegenerative diseases; respectively. p75NTR-/SOX2-positive cells may represent a promising therapeutical approach in inflammatory-degenerative CNS diseases.
- DDC subject of DNB:
- 630 Veterinary medicine & agriculture
- Dissertation note:
- Habilitationsschrift, Stiftung Tierärztliche Hochschule Hannover, 2016
Seehusen, Frauke Antje: Vergleichende Untersuchungen über die Pathogenese von Axonschäden und Remyelinisierung bei Enzephalitiden sowie genetischen Defekten des zentralen Nervensystems. Hannover 2017. Tierärztliche Hochschule.
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