Central nervous system pathology in MFP2 deficiency: Insights from general and conditional knockout mouse models

Verheijden, Simon; Beckers, Lien; Munter, Stephanie De; Veldhoven, Paul P. Van; Baes, Myriam

doi:10.1016/j.biochi.2013.08.009

Cited by 13 publications

(15 citation statements)

References 73 publications

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“…Patients with severe MFP2 deficiency suffer from neonatal hypotonia, brain malformations, seizures, and psychomotor retardation, and their life time typically does not exceed 1 y. [ 23 ]. Similarly, the KO mouse models manifest motor impairment, ataxia, and die within 6 mo.…”

Section: Discussionmentioning

confidence: 99%

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Precise Anatomic Localization of Accumulated Lipids in Mfp2 Deficient Murine Brains Through Automated Registration of SIMS Images to the Allen Brain Atlas

Škrášková

Khmelinskii

Abdelmoula

et al. 2015

J. Am. Soc. Mass Spectrom.

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Mass spectrometry imaging (MSI) is a powerful tool for the molecular characterization of specific tissue regions. Histochemical staining provides anatomic information complementary to MSI data. The combination of both modalities has been proven to be beneficial. However, direct comparison of histology based and mass spectrometry-based molecular images can become problematic because of potential tissue damages or changes caused by different sample preparation. Curated atlases such as the Allen Brain Atlas (ABA) offer a collection of highly detailed and standardized anatomic information. Direct comparison of MSI brain data to the ABA allows for conclusions to be drawn on precise anatomic localization of the molecular signal. Here we applied secondary ion mass spectrometry imaging at high spatial resolution to study brains of knock-out mouse models with impaired peroxisomal β-oxidation. Murine models were lacking D-multifunctional protein (MFP2), which is involved in degradation of very long chain fatty acids. SIMS imaging revealed deposits of fatty acids within distinct brain regions. Manual comparison of the MSI data with the histologic stains did not allow for an unequivocal anatomic identification of the fatty acids rich regions. We further employed an automated pipeline for co-registration of the SIMS data to the ABA. The registration enabled precise anatomic annotation of the brain structures with the revealed lipid deposits. The precise anatomic localization allowed for a deeper insight into the pathology of Mfp2 deficient mouse models.Graphical AbstractᅟElectronic supplementary materialThe online version of this article (doi:10.1007/s13361-015-1146-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

“…Similarly, the KO mouse models manifest motor impairment, ataxia, and die within 6 mo. [ 23 ]. Oil Red O staining of the brain sections of Mfp2 -/- mice showed significant lipid accumulation within several brain regions, most specifically within the ependymal cells of the whole ventricular system [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Precise Anatomic Localization of Accumulated Lipids in Mfp2 Deficient Murine Brains Through Automated Registration of SIMS Images to the Allen Brain Atlas

Škrášková

Khmelinskii

Abdelmoula

et al. 2015

J. Am. Soc. Mass Spectrom.

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“…Increased incorporation of VLCFAs into the phospholipids of the inner mitochondrial membrane might destabilize OXPHOS complexes inducing electron leakage and ROS production, finally compromising cell physiology (López-Erauskin et al 2013 ; Fourcade et al 2014 ). However, disease severity did not correlate with VLCFA elevation in the different conditional MFP2 −/− strains (Verheijden et al 2013 , 2014 ). Thus, accumulation of VLCFAs might not be mainly responsible for the ROS-induced and inflammatory pathology observed in many peroxisomal disorders.…”

Section: News From the Brain: Unravelling The Mysterious Role Of Peromentioning

confidence: 99%

The peroxisome: an update on mysteries 2.0

Islinger

Voelkl

Fahimi

et al. 2018

Histochem Cell Biol

234

227

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Peroxisomes are key metabolic organelles, which contribute to cellular lipid metabolism, e.g. the β-oxidation of fatty acids and the synthesis of myelin sheath lipids, as well as cellular redox balance. Peroxisomal dysfunction has been linked to severe metabolic disorders in man, but peroxisomes are now also recognized as protective organelles with a wider significance in human health and potential impact on a large number of globally important human diseases such as neurodegeneration, obesity, cancer, and age-related disorders. Therefore, the interest in peroxisomes and their physiological functions has significantly increased in recent years. In this review, we intend to highlight recent discoveries, advancements and trends in peroxisome research, and present an update as well as a continuation of two former review articles addressing the unsolved mysteries of this astonishing organelle. We summarize novel findings on the biological functions of peroxisomes, their biogenesis, formation, membrane dynamics and division, as well as on peroxisome–organelle contacts and cooperation. Furthermore, novel peroxisomal proteins and machineries at the peroxisomal membrane are discussed. Finally, we address recent findings on the role of peroxisomes in the brain, in neurological disorders, and in the development of cancer.

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“…There is no infiltration of peripheral monocytes, no systemic inflammation and no contribution of peripheral pathology to the clinical deterioration in Mfp2 −/− mice (Jia et al, 2003 ; Huyghe et al, 2006b , c ; Verheijden et al, 2013 , 2015 ). We previously generated a mouse model in which the HSD17B4 gene was conditionally inactivated in neural progenitor cells ( NestinCre + Mfp2 loxP/loxP , further denoted as Nestin-Mfp2 −/− mice) resulting in the complete depletion of the enzyme in neurons, astrocytes and oligodendrocytes (Verheijden et al, 2013 , 2014 ). Whereas constitutive Mfp2 −/− mice (further denoted as Mfp2 −/− ) develop chronic and extensive microgliosis and die within 4–6 months, Nestin-Mfp2 −/− mice only develop minor microgliosis and survive up to 12 months.…”

Section: Introductionmentioning

confidence: 99%

“…Whereas constitutive Mfp2 −/− mice (further denoted as Mfp2 −/− ) develop chronic and extensive microgliosis and die within 4–6 months, Nestin-Mfp2 −/− mice only develop minor microgliosis and survive up to 12 months. In contrast to the severe lethargic pathology in Mfp2 −/− mice, Nestin-Mfp2 −/− mice develop a milder clinical decline dominated by ataxia at a preterminal stage of disease (Verheijden et al, 2013 , 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Neuronal Dysfunction and Behavioral Abnormalities Are Evoked by Neural Cells and Aggravated by Inflammatory Microglia in Peroxisomal β-Oxidation Deficiency

Beckers

D’Hooge

Baes

2018

Front. Cell. Neurosci.

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It is becoming evident that microglia, the resident immune cells of the central nervous system (CNS), are active contributors in neurological disorders. Nevertheless, the impact of microgliosis on neuropathology, behavior and clinical decline in neuropathological conditions remains elusive. A mouse model lacking multifunctional protein-2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, develops a fatal disorder characterized by motor problems similar to the milder form of human disease. The molecular mechanisms underlying neurological decline in men and mice remain unknown. The hallmark of disease in the mouse model is chronic proliferation of microglia in the brain without provoking neuronal loss or demyelination. In order to define the contribution of Mfp2−/− neural cells to development of microgliosis and clinical neuropathology, the constitutive Mfp2−/− mouse model was compared to a neural selective Nestin-Mfp2−/− mouse model. We demonstrate in this study that, in contrast to early-onset and severe microgliosis in constitutive Mfp2−/− mice, Mfp2+/+ microglia in Nestin-Mfp2−/− mice only become mildly inflammatory at end stage of disease. Mfp2−/− microglia are primed and acquire a chronic and strong inflammatory state in Mfp2−/− mice whereas Mfp2+/+ microglia in Nestin-Mfp2−/− mice are not primed and adopt a minimal activation state. The inflammatory microglial phenotype in Mfp2−/− mice is correlated with more severe neuronal dysfunction, faster clinical deterioration and reduced life span compared to Nestin-Mfp2−/− mice. Taken together, our study shows that deletion of MFP2 impairs behavior and locomotion. Clinical decline and neural pathology is aggravated by an early-onset and excessive microglial response in Mfp2−/− mice and strongly indicates a cell-autonomous role of MFP2 in microglia.

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Central nervous system pathology in MFP2 deficiency: Insights from general and conditional knockout mouse models

Cited by 13 publications

References 73 publications

Precise Anatomic Localization of Accumulated Lipids in Mfp2 Deficient Murine Brains Through Automated Registration of SIMS Images to the Allen Brain Atlas

Precise Anatomic Localization of Accumulated Lipids in Mfp2 Deficient Murine Brains Through Automated Registration of SIMS Images to the Allen Brain Atlas

The peroxisome: an update on mysteries 2.0

Neuronal Dysfunction and Behavioral Abnormalities Are Evoked by Neural Cells and Aggravated by Inflammatory Microglia in Peroxisomal β-Oxidation Deficiency

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