Peroxisomen: organellen met een grote rol in de kleine hersenen

Een halve eeuw na hun ontdekking blijven peroxisomen mysterieuze organellen. Nochtans is het duidelijk dat deze celcompartimenten zowel in de vorming als in het behoud van de integriteit van het zenuwstelsel een essentiële rol spelen. Peroxisomale ziekten zijn zeldzame, erfelijke stofwisselingsziekten. De ernstige ziektebeelden, met het syndroom van Zellweger als prototype, zijn lethaal in de eerste levensjaren. De ontwikkeling van de hersenen is verstoord waarbij neuronen foutief gepositioneerd worden en de myelinatie vertraagd is. Ook een agressieve inflammatoire demyelinatie komt dikwijls voor. Deze patiënten kunnen eenduidig gediagnostiseerd worden op basis van metabole afwijkingen in het plasma. Recent werd aangetoond dat adolescente of volwassen patiënten met aspecifieke ziektebeelden, zoals cerebellaire ataxie of mentale retardatie, mutaties hadden in peroxisomale eiwitten. Het is intrigerend dat er in deze patiënten slechts geringe of geen metabole afwijkingen gevonden worden waardoor de pathogenese onduidelijk is. De verschillende peroxisomale ziekten werden nagebootst in muismodellen, wat moet toelaten om de ziektemechanismen te ontrafelen en eventuele therapieën te ontwikkelen.status: publishe

Peroxisomal Disorders: A Review on Cerebellar Pathologies

Peroxisomes are organelles with diverse metabolic tasks including essential roles in lipid metabolism. They are of utmost importance for the normal functioning of the nervous system as most peroxisomal disorders are accompanied with neurological symptoms. Remarkably, the cerebellum exquisitely depends on intact peroxisomal function both during development and adulthood. In this review, we cover all aspects of cerebellar pathology that were reported in peroxisome biogenesis disorders and in diseases caused by dysfunction of the peroxisomal α-oxidation, β-oxidation or ether lipid synthesis pathways. We also discuss the phenotypes of mouse models in which cerebellar pathologies were recapitulated and search for connections with the metabolic abnormalities. It becomes increasingly clear that besides the most severe forms of peroxisome dysfunction that are associated with developmental cerebellar defects, milder impairments can give rise to ataxia later in life.status: publishe

Autonomous Purkinje cell axonal dystrophy causes ataxia in peroxisomal multifunctional protein-2 deficiency

Background: Peroxisomes play a crucial role in normal neurodevelopment and in the maintenance of the adult brain. This depends largely on intact peroxisomal β-oxidation given the similarities in pathologies between peroxisome biogenesis disorders and deficiency of multifunctional protein-2 (MFP2), the central enzyme of this pathway. Recently, adult patients diagnosed with cerebellar ataxia were shown to have mild mutations in the MFP2 gene, hydroxy-steroid dehydrogenase (17 beta) type 4 (HSD17B4). Cerebellar atrophy also develops in MFP2 deficient mice but the cellular origin of the degeneration is unexplored. Methods: In order to investigate whether peroxisomal β-oxidation is essential within Purkinje cells, the sole output neurons of the cerebellum, we generated and characterized a mouse model with Purkinje cell selective deletion of the MFP2 gene. Results: We show that selective loss of MFP2 from mature cerebellar Purkinje neurons causes a late-onset motor phenotype and progressive Purkinje cell degeneration, thereby mimicking ataxia and cerebellar deterioration in patients with mild HSD17B4 mutations. We demonstrate that swellings on Purkinje cell axons coincide with ataxic behavior and precede neurodegeneration. Loss of Purkinje cells occurs in a characteristic banded pattern, proceeds in an anterior to posterior fashion and is accompanied by progressive astro- and microgliosis. Conclusions: These data prove that the peroxisomal β-oxidation pathway is required within Purkinje neurons to maintain their axonal integrity, independent of glial dysfunction.status: publishe

Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency

The cerebellar pathologies in peroxisomal diseases underscore that these organelles are required for the normal development and maintenance of the cerebellum, but the mechanisms have not been resolved. Here we investigated the origins of the early-onset coordination impairment in a mouse model with neural selective deficiency of multifunctional protein-2, the central enzyme of peroxisomal β-oxidation. At the age of 4 weeks, Nestin-Mfp2−/− mice showed impaired motor learning on the accelerating rotarod and underperformed on the balance beam test. The gross morphology of the cerebellum and Purkinje cell arborization were normal. However, electrophysiology revealed a reduced Purkinje cell firing rate, a decreased excitability and an increased membrane capacitance. The distribution of climbing and parallel fiber synapses on Purkinje cells was immature and was accompanied by an increased spine length. Despite normal myelination, Purkinje cell axon degeneration was evident from the occurrence of axonal swellings containing accumulated organelles. In conclusion, the electrical activity, axonal integrity and wiring of Purkinje cells are exquisitely dependent on intact peroxisomal β-oxidation in neural cells.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

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

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.status: publishe

Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency

The cerebellar pathologies in peroxisomal diseases underscore that these organelles are required for the normal development and maintenance of the cerebellum, but the mechanisms have not been resolved. Here we investigated the origins of the early-onset coordination impairment in a mouse model with neural selective deficiency of multifunctional protein-2, the central enzyme of peroxisomal β-oxidation. At the age of 4weeks, Nestin-Mfp2(-/-) mice showed impaired motor learning on the accelerating rotarod and underperformed on the balance beam test. The gross morphology of the cerebellum and Purkinje cell arborization were normal. However, electrophysiology revealed a reduced Purkinje cell firing rate, a decreased excitability and an increased membrane capacitance. The distribution of climbing and parallel fiber synapses on Purkinje cells was immature and was accompanied by an increased spine length. Despite normal myelination, Purkinje cell axon degeneration was evident from the occurrence of axonal swellings containing accumulated organelles. In conclusion, the electrical activity, axonal integrity and wiring of Purkinje cells are exquisitely dependent on intact peroxisomal β-oxidation in neural cells.publisher: Elsevier articletitle: Early-onset Purkinje cell dysfunction underlies cerebellar ataxia in peroxisomal multifunctional protein-2 deficiency journaltitle: Neurobiology of Disease articlelink: http://dx.doi.org/10.1016/j.nbd.2016.06.012 content_type: article copyright: © 2016 Elsevier Inc. All rights reserved.status: publishe

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

Proteomic