Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability, motor impairment, and premature death. There is currently no cure or corrective treatment. The disease results from mutations in the gene encoding mucolipin-1, a transient receptor potential channel believed to play a key role in lysosomal calcium egress. Loss of mucolipin-1 and subsequent defects lead to a host of cellular aberrations, including accumulation of glycosphingolipids (GSLs) in neurons and other cell types, microgliosis and, as reported here, cerebellar Purkinje cell loss. Several studies have demonstrated that N-butyldeoxynojirimycin (NB-DNJ, also known as miglustat), an inhibitor of the enzyme glucosylceramide synthase (GCS), successfully delays the onset of motor deficits, improves longevity, and rescues some of the cerebellar abnormalities (e.g., Purkinje cell death) seen in another lysosomal disease known as Niemann-Pick type C (NPC). Given the similarities in pathology between MLIV and NPC, we examined whether miglustat would be efficacious in ameliorating disease progression in MLIV. Using a full mucolipin-1 knockout mouse (Mcoln1-/-), we found that early miglustat treatment delays the onset and progression of motor deficits, delays cerebellar Purkinje cell loss, and reduces cerebellar microgliosis characteristic of MLIV disease. Quantitative mass spectrometry analyses provided new data on the GSL profiles of murine MLIV brain tissue and showed that miglustat partially restored the wild type profile of white matter enriched lipids. Collectively, our findings indicate that early miglustat treatment delays the progression of clinically relevant pathology in an MLIV mouse model, and therefore supports consideration of miglustat as a therapeutic agent for MLIV disease in humans.

• Klíčová slova
• Glycosphingolipids, Lysosomal storage disease, Miglustat, Mucolipidosis type IV, Mucolipin-1, Purkinje cells, Small molecule therapy,
• MeSH
• 1-deoxynojirimycin analogy a deriváty   terapeutické užití   MeSH
• CD antigeny metabolismus   MeSH
• glióza farmakoterapie   etiologie   MeSH
• inhibitory enzymů terapeutické užití   MeSH
• kationtové kanály TRP genetika   metabolismus   MeSH
• metabolismus lipidů účinky léků   genetika   MeSH
• modely nemocí na zvířatech MeSH
• mozeček patologie   MeSH
• mukolipidózy * komplikace   genetika   patologie   MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• pátrací chování účinky léků   MeSH
• počet buněk MeSH
• pohybové poruchy farmakoterapie   etiologie   MeSH
• proteiny nervové tkáně metabolismus   MeSH
• psychomotorický výkon účinky léků   MeSH
• Purkyňovy buňky účinky léků   patologie   MeSH
• retina patologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 1-deoxynojirimycin MeSH
• CD antigeny MeSH
• inhibitory enzymů MeSH
• kationtové kanály TRP MeSH
• Mcoln1 protein, mouse MeSH Prohlížeč
• miglustat MeSH Prohlížeč
• proteiny nervové tkáně MeSH

Christianson syndrome (CS) is an X-linked neurodevelopmental and neurological disorder characterized in males by core symptoms that include non-verbal status, intellectual disability, epilepsy, truncal ataxia, postnatal microcephaly and hyperkinesis. CS is caused by mutations in the SLC9A6 gene, which encodes a multipass transmembrane sodium (potassium)-hydrogen exchanger 6 (NHE6) protein, functional in early recycling endosomes. The extent and variability of the CS phenotype in female heterozygotes, who presumably express the wild-type and mutant SLC9A6 alleles mosaically as a result of X-chromosome inactivation (XCI), have not yet been systematically characterized. Slc9a6 knockout mice (Slc9a6 KO) were generated by insertion of the bacterial lacZ/β-galactosidase (β-Gal) reporter into exon 6 of the X-linked gene. Mutant Slc9a6 KO male mice have been shown to develop late endosomal/lysosomal dysfunction associated with glycolipid accumulation in selected neuronal populations and patterned degeneration of Purkinje cells (PCs). In heterozygous female Slc9a6 KO mice, β-Gal serves as a transcriptional/XCI reporter and thus facilitates testing of effects of mosaic expression of the mutant allele on penetrance of the abnormal phenotype. Using β-Gal, we demonstrated mosaic expression of the mutant Slc9a6 allele and mosaically distributed lysosomal glycolipid accumulation and PC pathology in the brains of heterozygous Slc9a6 KO female mice. At the behavioral level, we showed that heterozygous female mice suffer from visuospatial memory and motor coordination deficits similar to but less severe than those observed in X-chromosome hemizygous mutant males. Our studies in heterozygous Slc9a6 KO female mice provide important clues for understanding the likely phenotypic range of Christianson syndrome among females heterozygous for SLC9A6 mutations and might improve diagnostic practice and genetic counseling by helping to characterize this presumably underappreciated patient/carrier group.

• Klíčová slova
• Christianson syndrome, Female heterozygotes, Mosaicism, NHE6 protein, Slc9a6, X-chromosome inactivation,
• MeSH
• alely MeSH
• ataxie genetika   MeSH
• chování zvířat MeSH
• epilepsie genetika   MeSH
• fenotyp MeSH
• G(M2) gangliosid imunologie   MeSH
• genetické nemoci vázané na chromozom X genetika   MeSH
• genotyp MeSH
• heterozygot MeSH
• kognitivní poruchy genetika   MeSH
• mentální retardace genetika   MeSH
• mikrocefalie genetika   MeSH
• modely nemocí na zvířatech MeSH
• mozaicismus * MeSH
• mutace MeSH
• myši knockoutované MeSH
• myši MeSH
• Na(+)-H(+) antiport genetika   fyziologie   MeSH
• poruchy hybnosti oka genetika   MeSH
• Purkyňovy buňky cytologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• G(M2) gangliosid MeSH
• Na(+)-H(+) antiport MeSH
• NHE6 protein, mouse MeSH Prohlížeč

Chromatin compaction mediates progenitor to post-mitotic cell transitions and modulates gene expression programs, yet the mechanisms are poorly defined. Snf2h and Snf2l are ATP-dependent chromatin remodelling proteins that assemble, reposition and space nucleosomes, and are robustly expressed in the brain. Here we show that mice conditionally inactivated for Snf2h in neural progenitors have reduced levels of histone H1 and H2A variants that compromise chromatin fluidity and transcriptional programs within the developing cerebellum. Disorganized chromatin limits Purkinje and granule neuron progenitor expansion, resulting in abnormal post-natal foliation, while deregulated transcriptional programs contribute to altered neural maturation, motor dysfunction and death. However, mice survive to young adulthood, in part from Snf2l compensation that restores Engrailed-1 expression. Similarly, Purkinje-specific Snf2h ablation affects chromatin ultrastructure and dendritic arborization, but alters cognitive skills rather than motor control. Our studies reveal that Snf2h controls chromatin organization and histone H1 dynamics for the establishment of gene expression programs underlying cerebellar morphogenesis and neural maturation.

• MeSH
• adenosintrifosfatasy metabolismus   MeSH
• analýza rozptylu MeSH
• bromodeoxyuridin MeSH
• chromatinová imunoprecipitace MeSH
• chromozomální proteiny, nehistonové metabolismus   MeSH
• fluorescence MeSH
• galaktosidy MeSH
• histony metabolismus   MeSH
• homeodoménové proteiny metabolismus   MeSH
• hybridizace in situ MeSH
• imunohistochemie MeSH
• indoly MeSH
• koncové značení zlomů DNA in situ MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• metoda rotující tyčky MeSH
• mikročipová analýza MeSH
• morfogeneze genetika   fyziologie   MeSH
• mozeček embryologie   MeSH
• myši transgenní MeSH
• myši MeSH
• nervové kmenové buňky metabolismus   fyziologie   MeSH
• počítačové zpracování obrazu MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• Purkyňovy buňky metabolismus   MeSH
• restrukturace chromatinu fyziologie   MeSH
• toloniumchlorid MeSH
• transmisní elektronová mikroskopie MeSH
• vývojová regulace genové exprese genetika   fyziologie   MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• 5-bromo-4-chloro-3-indolyl beta-galactoside MeSH Prohlížeč
• adenosintrifosfatasy MeSH
• bromodeoxyuridin MeSH
• chromozomální proteiny, nehistonové MeSH
• En1 protein, mouse MeSH Prohlížeč
• galaktosidy MeSH
• histony MeSH
• homeodoménové proteiny MeSH
• indoly MeSH
• Smarca5 protein, mouse MeSH Prohlížeč
• toloniumchlorid MeSH