Cln5-deficiency in mice leads to microglial activation, defective myelination and changes in lipid metabolism

Schmiedt, Mia-Lisa; Blom, Tea; Blom, Tomas; Kopra, Outi; Wong, Andrew; Schantz-Fant, Carina von; Ikonen, Elina; Kuronen, Mervi; Jauhiainen, Matti; Cooper, Jonathan D.; Jalanko, Anu

doi:10.1016/j.nbd.2011.12.009

Cited by 44 publications

(70 citation statements)

References 72 publications

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“…Activation of astrocytes has also been reported in the only brain autopsy case described in MLIV [9], where, based on general observations of reactive astrocytes accompanying neuronal death in other neurodegenerative conditions, it was thought to mark neuronal loss. Reactive astrocytes and microgliosis have been observed in mouse models of other LSDs, including the NCLs [27],[38]–[43], mucopolysaccharidosises [44]; Neimann-Pick disease [45] and mucolipidosis II [46]. In many of these models, neuroinflammation develops early and precedes neuronal loss in the gliosis-affected brain regions.…”

Section: Discussionmentioning

confidence: 99%

Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV

Grishchuk

Sri

Rudinskiy

et al. 2014

acta neuropathol commun

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Mucolipidosis IV (MLIV) is caused by mutations in the gene MCOLN1. Patients with MLIV have severe neurologic deficits and very little is known about the brain pathology in this lysosomal disease. Using an accurate mouse model of mucolipidosis IV, we observed early behavioral deficits which were accompanied by activation of microglia and astrocytes. The glial activation that persisted during the course of disease was not accompanied by neuronal loss even at the late stage. In vivo [Ca2+]-imaging revealed no changes in resting [Ca2+] levels in Mcoln1−/− cortical neurons, implying their physiological health. Despite the absence of neuron loss, we observed alterations in synaptic plasticity, as indicated by elevated paired-pulse facilitation and enhanced long-term potentiation. Myelination deficits and severely dysmorphic corpus callosum were present early and resembled white matter pathology in mucolipidosis IV patients. These results indicate the early involvement of glia, and challenge the traditional view of mucolipidosis IV as an overtly neurodegenerative condition.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0133-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV

Grishchuk

Sri

Rudinskiy

et al. 2014

acta neuropathol commun

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“…Studies with the CLN5-knockout mice have provided insights into the nature and spatiotemporal distribution of histopathologic and biochemical lesions during disease development [37,52,53]. Nonetheless, large animal models are often preferable to rodents for investigating therapeutic interventions for neurodegenerative diseases because their gyrencephalic brains are more similar to human brains in size and complexity and because the durations of clinical signs for the large animal model diseases are closer to those of the human diseases.…”

Section: Animal Models For Cln5mentioning

confidence: 99%

Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5

Gilliam

Kolicheski

Johnson

et al. 2015

Molecular Genetics and Metabolism

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We studied a recessive, progressive neurodegenerative disease occurring in Golden Retriever siblings with an onset of signs at 15 months of age. As the disease progressed these signs included ataxia, anxiety, pacing and circling, tremors, aggression, visual impairment and localized and generalized seizures. A whole genome sequence, generated with DNA from one affected dog, contained a plausibly causal homozygous mutation: CLN5:c.934_935delAG. This mutation was predicted to produce a frameshift and premature termination codon and encode a protein variant, CLN5:p.E312Vfs*6, which would lack 39 C-terminal amino acids. Eighteen DNA samples from the Golden Retriever family members were genotyped at CLN5:c.934_935delAG. Three clinically affected dogs were homozygous for the deletion allele; whereas, the clinically normal family members were either heterozygotes (n = 11) or homozygous for the reference allele (n = 4). Among archived Golden Retrievers DNA samples with incomplete clinical records that were also genotyped at the CLN5:c.934_935delAG variant, 1053 of 1062 were homozygous for the reference allele, 8 were heterozygotes and one was a deletion-allele homozygote. When contacted, the owner of this homozygote indicated that their dog had been euthanized because of a neurologic disease that progressed similarly to that of the affected Golden Retriever siblings. We have collected and stored semen from a heterozygous Golden Retriever, thereby preserving an opportunity for us or others to establish a colony of CLN5-deficient dogs.

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“…We previously generated a Cln5 knock-out (ko) mouse model [14] which presents a relatively late onset neurodegenerative disease phenotype with visual/cognitive dysfunction, progressive accumulation of autofluorescent storage material, loss of GABAergic interneurons, synaptic pathology, and a marked glial activation and hypomyelination preceding neuronal loss, mostly pronounced in the thalamocortical system [14,15,16]. In addition, Cln5 ko mice suffer from several neurological defects, including mild motor dysfunction, and exhibit progressive weight loss and brain atrophy [14].…”

Section: Introductionmentioning

confidence: 99%

“…The CLN5 protein is a soluble lysosomal glycoprotein [17,18] that is expressed ubiquitously, including in neurons and glia [15,19]. The function of the CLN5 protein is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that CLN1 and CLN5 share a common interaction partner, the F1 subunit of the ATP synthase [24,25], a well-known mitochondrial protein, also implicated in the function of cholesterol transport across the plasma membrane [26]. The involvement of both CLN5 and CLN1 in cholesterol metabolism is also suggested by observed abnormalities in the cellular and systemic lipid metabolism in the corresponding mouse models [15,25,27]. Furthermore, Cln5 ko mice exhibit disturbances in intracellular sphingolipid transport, studied using a fluorescent sphingolipid analogue, BODIPY FL C5-lactosylceramide [15].…”

Section: Introductionmentioning

confidence: 99%

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Induced Pluripotent Stem Cells Derived from a CLN5 Patient Manifest Phenotypic Characteristics of Neuronal Ceroid Lipofuscinoses

Uusi-Rauva

Blom

Schantz-Fant

et al. 2017

IJMS

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Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive progressive encephalopathies caused by mutations in at least 14 different genes. Despite extensive studies performed in different NCL animal models, the molecular mechanisms underlying neurodegeneration in NCLs remain poorly understood. To model NCL in human cells, we generated induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblasts from a patient with CLN5 (ceroid lipofuscinosis, neuronal, 5) disease, the late infantile variant form of NCL. These CLN5 patient-derived iPSCs (CLN5Y392X iPSCs) harbouring the most common CLN5 mutation, c.1175_1176delAT (p.Tyr392X), were further differentiated into neural lineage cells, the most affected cell type in NCLs. The CLN5Y392X iPSC-derived neural lineage cells showed accumulation of autofluorescent storage material and subunit C of the mitochondrial ATP synthase, both representing the hallmarks of many forms of NCLs, including CLN5 disease. In addition, we detected abnormalities in the intracellular organelles and aberrations in neuronal sphingolipid transportation, verifying the previous findings obtained from Cln5-deficient mouse macrophages. Therefore, patient-derived iPSCs provide a suitable model to study the mechanisms of NCL diseases.

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Cln5-deficiency in mice leads to microglial activation, defective myelination and changes in lipid metabolism

Cited by 44 publications

References 72 publications

Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV

Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV

Golden Retriever dogs with neuronal ceroid lipofuscinosis have a two-base-pair deletion and frameshift in CLN5

Induced Pluripotent Stem Cells Derived from a CLN5 Patient Manifest Phenotypic Characteristics of Neuronal Ceroid Lipofuscinoses

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