Immunohistochemical and transcriptome analyses indicate complex breakdown of axonal transport mechanisms in canine distemper leukoencephalitis

Spitzbarth, Ingo; Lempp, Charlotte; Kegler, Kristel; Ulrich, Reiner; Kalkuhl, Arno; Deschl, Ulrich; Baumgärtner, Wolfgang; Seehusen, Frauke

doi:10.1002/brb3.472

Cited by 7 publications

(16 citation statements)

References 66 publications

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“…Therefore, it can be assumed that their immunoreactivity indicates their axonal localization. These findings indicate that the accumulation of lysosomal storage material might influence axonal transport and neurofilament phosphorylation status [75,76,88,89,103]. A disturbance in the kinesin-mediated transport of dynein could also affect dynein distribution, because dynein transport is also partly dependent on kinesin (direct transport) [104].…”

Section: Discussionmentioning

confidence: 92%

“…NF phosphorylation also controls the association of NFs with kinesin and dynein, and thereby their own axonal transport [100,101]. Thus, alterations in the amount and distribution of β-APP, pNF, nNF, kinesin, and dynein can be used as surrogate markers for axonal damage and disturbed axonal transport [75,76,88,102,103]. Furthermore, the antibodies are restricted to axons only in the CNS.…”

Section: Discussionmentioning

confidence: 99%

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Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Eikelberg¹,

Lehmbecker²,

Brogden³

et al. 2020

JCM

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GM1-gangliosidosis is caused by a reduced activity of β-galactosidase (Glb1), resulting in intralysosomal accumulations of GM1. The aim of this study was to reveal the pathogenic mechanisms of GM1-gangliosidosis in a new Glb1 knockout mouse model. Glb1−/− mice were analyzed clinically, histologically, immunohistochemically, electrophysiologically and biochemically. Morphological lesions in the central nervous system were already observed in two-month-old mice, whereas functional deficits, including ataxia and tremor, did not start before 3.5-months of age. This was most likely due to a reduced membrane resistance as a compensatory mechanism. Swollen neurons exhibited intralysosomal storage of lipids extending into axons and amyloid precursor protein positive spheroids. Additionally, axons showed a higher kinesin and lower dynein immunoreactivity compared to wildtype controls. Glb1−/− mice also demonstrated loss of phosphorylated neurofilament positive axons and a mild increase in non-phosphorylated neurofilament positive axons. Moreover, marked astrogliosis and microgliosis were found, but no demyelination. In addition to the main storage material GM1, GA1, sphingomyelin, phosphatidylcholine and phosphatidylserine were elevated in the brain. In summary, the current Glb1−/− mice exhibit a so far undescribed axonopathy and a reduced membrane resistance to compensate the functional effects of structural changes. They can be used for detailed examinations of axon–glial interactions and therapy trials of lysosomal storage diseases.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Eikelberg¹,

Lehmbecker²,

Brogden³

et al. 2020

JCM

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“…These results indicate that the phosphorylation status of neurofilaments is affected by a combination of NGF and G M1 ganglioside. The changes in the neuronal cytoskeleton might affect axonal transport mechanisms and synaptic plasticity 65,66 . Therefore, the expression of the cytoskeletal motor proteins dynein and kinesin and synaptophysin, a synaptic vesicle glycoprotein was investigated.…”

Section: G M1 and Growth Factors Differentially Affect The Neuronal Cmentioning

confidence: 99%

Neurotrophic effects of GM1 ganglioside, NGF, and FGF2 on canine dorsal root ganglia neurons in vitro

Schwarz¹,

Lehmbecker²,

Tongtako

et al. 2020

Sci Rep

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certain growth factors 23. Gangliosides are sialic acid-containing glycosphingolipids that can be found in different cellular membranes. In the CNS gangliosides account for up to 10% of the total lipid content in neurons 24. They are involved in intercellular communication, cellular differentiation, neuronal development, and regeneration 25-28 due to their capacity to modulate Ca 2+ influx and their influence on the function of receptors for muscarinic acetylcholine, serotonin, glutamine, neurotransmitters, and neurotrophic factors 29. Cellular gangliosides concentrate in lipid microdomains termed lipid rafts, which are signaling platforms rich in cholesterol and glycosphingolipids and contain amongst others high affinity tropomyosin-related kinase (Trk) and low affinity neurotrophin receptors (p75 NTR) 30-32. These receptors are activated by nerve growth factor (NGF) and other neurotrophic factors and have a strong impact on neuronal development, maintenance, and survival as well as memory formation and storage 33,34. Anti-G M1 antibodies modulate the membrane-associated sphingomyelin metabolism by altering neutral sphingomyelinase activity thereby inhibiting NGF action on rat pheochromocytoma (PC12) cells 35,36. G M1 and NGF protect primary cultured rat embryonic dorsal root ganglia (DRG) and spinal cord neurons from glutamate-induced excitotoxicity 37,38. Both molecules may function by modulating Ca 2+ homeostasis, maintaining normal mitochondrial membrane potential or by promoting the mRNA expression of neuronal proteins such as growth associated protein 43 and neurofilaments (NFs) 38,39. G M1 also protects rats against high altitude cerebral edema by suppressing oxidative stress and production of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α 40. Nevertheless, another study using an ischemia/reperfusion model in rats demonstrated that G M1 neuroprotection seems to be dependent on p75 NTR 41. Exogenous gangliosides also directly interact with growth factors such as basic fibroblast growth factor (FGF2) and inhibit FGF receptor binding 42,43. Moreover, G M1 can inhibit FGF2-mediated effects by acting on the same intracellular signaling molecules. For instance, FGF2 stimulates the activity of glycogen synthase kinase 3 (GSK3) in proliferating adult rat hippocampal progenitor cells, whereas G M1 prevents GSK3 activation in organotypic hippocampal slice cultures 44,45. In contrast, cell-associated G M1 has been described to act as a functional co-receptor for FGF2 43. Despite its name, FGF2 plays an essential role in neurogenesis, differentiation, axonal branching, and neuron survival in various types of brain and peripheral nerve lesions 46,47. FGF2 also stimulates the proliferation of neuronal precursor cells isolated from postnatal murine DRGs 48. The ability of adult rat ganglion cells to regrow axons in vitro can be influenced by FGF2 and G M1 49. Neurotrophic effects of FGF2 seem to be also mediated by soluble mediators released from glial cells 50. Summarized, NGF, FGF2 and gangliosides such as G M1 ...

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“…In subacute lesions, there is an occurrence of p75 NTR -positive cells, possibly representing a pre-myelinating stage of Schwann cells [ 24 ]. Nevertheless, only single periaxin-positive cells which are suggestive of manifest Schwann cell remyelination, were detected within few advanced lesions [ 25 ]. Furthermore, it was also shown that following extensive axonal degeneration the axonal expression of GAP43, indicative of axonal regeneration, failed to reach the level of significance in dogs with CDV-DL [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, only single periaxin-positive cells which are suggestive of manifest Schwann cell remyelination, were detected within few advanced lesions [ 25 ]. Furthermore, it was also shown that following extensive axonal degeneration the axonal expression of GAP43, indicative of axonal regeneration, failed to reach the level of significance in dogs with CDV-DL [ 25 ]. The up-regulation of ECM molecules, especially of chondroitin sulfate proteoglycans, after CNS injury is known to impair axonal sprouting and inhibit remyelination by oligodendroglial cells [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Accumulation of Extracellular Matrix in Advanced Lesions of Canine Distemper Demyelinating Encephalitis

et al. 2016

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In demyelinating diseases, changes in the quality and quantity of the extracellular matrix (ECM) may contribute to demyelination and failure of myelin repair and axonal sprouting, especially in chronic lesions. To characterize changes in the ECM in canine distemper demyelinating leukoencephalitis (DL), histochemical and immunohistochemical investigations of formalin-fixed paraffin-embedded cerebella using azan, picrosirius red and Gomori`s silver stain as well as antibodies directed against aggrecan, type I and IV collagen, fibronectin, laminin and phosphacan showed alterations of the ECM in CDV-infected dogs. A significantly increased amount of aggrecan was detected in early and late white matter lesions. In addition, the positive signal for collagens I and IV as well as fibronectin was significantly increased in late lesions. Conversely, the expression of phosphacan was significantly decreased in early and more pronounced in late lesions compared to controls. Furthermore, a set of genes involved in ECM was extracted from a publically available microarray data set and was analyzed for differential gene expression. Gene expression of ECM molecules, their biosynthesis pathways, and pro-fibrotic factors was mildly up-regulated whereas expression of matrix remodeling enzymes was up-regulated to a relatively higher extent. Summarized, the observed findings indicate that changes in the quality and content of ECM molecules represent important, mainly post-transcriptional features in advanced canine distemper lesions. Considering the insufficiency of morphological regeneration in chronic distemper lesions, the accumulated ECM seems to play a crucial role upon regenerative processes and may explain the relatively small regenerative potential in late stages of this disease.

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Immunohistochemical and transcriptome analyses indicate complex breakdown of axonal transport mechanisms in canine distemper leukoencephalitis

Cited by 7 publications

References 66 publications

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Neurotrophic effects of GM1 ganglioside, NGF, and FGF2 on canine dorsal root ganglia neurons in vitro

Accumulation of Extracellular Matrix in Advanced Lesions of Canine Distemper Demyelinating Encephalitis

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