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Accumulation and distribution of ?-synuclein and ubiquitin in the CNS of Gaucher disease mouse models.

ABSTRACT: Gaucher disease, a prevalent lysosomal storage disease, is caused by insufficient activity of acid ?-glucosidase (GCase) and resultant glucosylceramide accumulation. Recently in Parkinson disease (PD) patients, heterozygous mutations in GCase have been associated with earlier onset and more progressive PD. To understand the pathogenic relationships between GCase variants and Parkinsonism, ?-synuclein and ubiquitin distributions and levels in the brains of several mouse models containing GCase variants were evaluated by immunohistochemistry. Progressive ?-synuclein and ubiquitin aggregate accumulations were observed in the cortex, hippocampus, basal ganglia, brainstem, and some cerebellar regions between 4 and 24 weeks in mice that were homozygous for GCase [D409H (9H) or V394L (4L)] variants and also had a prosaposin hypomorphic (PS-NA) transgene. In 4L/PS-NA and 9H/PS-NA mice, this was coincident with progressive neurological manifestations and brain glucosylceramide accumulation. Ultrastructural studies showed electron dense inclusion bodies in neurons and axons of 9H/PS-NA brains. ?-synuclein aggregates were also observed in ventricular, brainstem, and cerebellar regions of older mice (>42-weeks) with the GCase variant (D409H/D409H) without overt neurological disease. In a chemically induced GCase deficiency, ?-synuclein aggregates and glucosylceramide accumulation also occurred. These studies demonstrate a relationship between glucosylceramide accumulation and ?-synuclein aggregates, and implicate glucosylceramide accumulation as risk factor for the ?-synucleinopathies.

SUBMITTER: Xu YH

PROVIDER: S-EPMC3059359 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Accumulation and distribution of α-synuclein and ubiquitin in the CNS of Gaucher disease mouse models.

Xu Y H YH Sun Y Y Ran H H Quinn B B Witte D D Grabowski G A GA

Molecular genetics and metabolism 20101231 4

Gaucher disease, a prevalent lysosomal storage disease, is caused by insufficient activity of acid β-glucosidase (GCase) and resultant glucosylceramide accumulation. Recently in Parkinson disease (PD) patients, heterozygous mutations in GCase have been associated with earlier onset and more progressive PD. To understand the pathogenic relationships between GCase variants and Parkinsonism, α-synuclein and ubiquitin distributions and levels in the brains of several mouse models containing GCase va ...[more]

PMID: 21257328

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Project description:Purpose: In order to describe how non- genetic factors may contribute to emergence of additional neurodegenerative disorders in mice with neuronal Gaucher Disease (nGD), full transcript mRNA sequencing was implemented with half brain in order to study differential gene expression between experimental groups: (Untreated) Control, CBE (Conduritol β epoxide ), SVNI (Sindbis virus), and CBE + SVNI Methods: Full transcript mRNA sequencing was implemented with half brain in order to study differential gene expression between experimental groups (biologilal triplicates in each group). We mapped 20 million sequence reads per sample to the mouse genome (GRCm38) and identified 16,903 transcripts. . All subjects were 28 days old. Half of the bisected brains were flash-frozen in liquid nitrogen and stored in -80C conditions until use. RNA was isolated using a RNeasy mini kit (Qiagen, Hilden, Germany). Extraction of RNA was performed at the Israeli Institute for Biological Research and the RNA was then transferred to the Weizmann Institute of Science for further analysis. Quality was examined with the Agilent 2200 TapeStation system (Agilent Technologies); RIN values of each sample were determined satisfactory for use in sequencing. Expression of mRNA was quantified using DESeq following normalization of library size with Pipeline. Gene lists were created by criteria based on an absolute linear fold change ≥ 2.0, *p ≤ 0.05. Enriched pathways in the resulting gene lists were analyzed with Ingenuity Pathway Analysis (IPA). Results: Our study represents the first full RNA transcriptome analysis of brains from of CBE-treated mice, with biological triplicates generated by RNA-seq technology. The CBE and CBE+SVNI conditions boast remarkably similar genetic profiles with no differentially expressed genes changed between them (fold change ≥ 2.0, *p ≤ 0.05). In CBE, SVNI, and CBE + SVNI conditions respectively, 501, 1724, and 554 genes were significantly upregulated compared to the control, while 5, 333, and 40 genes were significantly downregulated respectively (Fig. 2B). Surprisingly, 476 upregulated genes in the CBE condition were shared with SVNI, while only 25 genes were uniquely upregulated. No downregulated genes were shared between the two conditions (Fig. 2C). Here, we conclude that CBE and CBE+SVNI demonstrate nearly identical mRNA profiles while SVNI boasted highly differential genes compared to all other conditions. Conclusion: Half brain mRNA profiles of 28-day old untreated (Control), CBE-treated, SVNI-treated, and SVNI + CBE-treated mice were generated by deep sequencing, in triplicate, using Illumina Hiseq.

Dataset Information

Accumulation and distribution of ?-synuclein and ubiquitin in the CNS of Gaucher disease mouse models.

Publications

Accumulation and distribution of α-synuclein and ubiquitin in the CNS of Gaucher disease mouse models.

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