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Exacerbated neuronal ceroid lipofuscinosos phenotype in Cln1/5 double knock-out mice

ABSTRACT: Both CLN1 and CLN5 deficiency leads to severe neurodegenerative diseases of childhood, known as neuronal ceroid lipofuscinoses (NCL). The broadly similar phenotypes of NCL mouse models, and the potential for interactions between NCL proteins, raise the possibility of shared or converging disease mechanisms. To begin addressing these issues we have developed a novel mouse model lacking both Cln1 and Cln5 genes. These Cln1/5 double knock-out (Cln1/5 dko) mice were fertile, showing a slight decrease in expected Mendelian breeding ratios, as well as impaired embryoid body formation of induced pluripotent stem cells derived from Cln1/5 dko fibroblasts. Typical manifestations of the NCL diseases, seizures and motor dysfunction, were detected at the age of 3 months, earlier than in either single knock-out mouse. Pathological analyses revealed a similar exacerbation and earlier onset of disease in Cln1/5 dko mice, which exhibit a pronounced accumulation of autofluorescent storage material. Cortical demyelination and more pronounced glial activation in cortical and thalamic regions was followed by cortical neuron loss. Alterations in lipid metabolism in Cln1/5 dko showed specifically an increase in serum phospholipid transfer protein (PLTP) activity. Finally, gene expression profiling of Cln1/5 dko cortex revealed defects in myelination and immune response pathways, with a prominent downregulation of alpha-synuclein in Cln1/5 dko mouse brains. The simultaneous loss of both Cln1 and Cln5 genes may enhance the typical pathological phenotypes of these mice by disrupting down shared or convergent pathogenic pathways, which may potentially include interactions of CLN1 and CLN5.

ORGANISM(S): Mus musculus

PROVIDER: GSE37643 | GEO | 2012/10/31

SECONDARY ACCESSION(S): PRJNA162369

REPOSITORIES: GEO

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Project description:The trimeric thrombospondin homologs, TSP1 and TSP2, are both components of bone tissue and contribute in redundant and distinct ways to skeletal physiology. The functional effects of combined TSP1 and TSP2 deficiency remain to be elucidated. Here, we examined the spectrum of detergent soluble proteins in diaphyseal cortical bone of growing (6-week old) male and female mice deficient in both thrombospondins (double knockout (DKO)). Equal amounts of detergent soluble cortical bone protein were subject to Tandem Mass Tags (TMT) quantitative proteomics. 3,429 proteins met the selection criteria (FDR≤ 1% and 2 peptide spectral matches). 181 proteins were differentially abundant in both male and female DKO bones (≥1.95 fold or ≤0.55 fold compared to wild-type). Physiologically relevant annotation terms identified by Ingenuity Pathway Analysis included “ECM degradation” and “Quantity of Monocytes.” Manual inspection revealed that a number of proteins with shared expression among osteoclasts and osteocytes were reduced in DKO bones. To associate changes in protein content with phenotype, we examined 12-week old male DKO and WT mice. DKO mice were smaller than WT. DKO femora had reduced cross-sectional area with a flattened, less circular cross-section. DKO bones were less stiff in bending, but this reduction was disproportionate to the decreases in bending moment of inertia on nanoCT leading to a modest increase in predicted modulus (stiffness/bending moment). DKO displayed a lower ultimate load along with increases in both ultimate displacement and yield displacement. The ratio of ultimate displacement to yield displacement was actually higher in DKO, suggesting that decreased yield displacement does not account entirely for the reduction in ultimate displacement. Together, these mechanical attributes suggest compensation for small bone size through mechanisms that are not explained by nanoCT structural analysis. DKO mice also exhibited reductions in trabecular bone mass, which were surprisingly associated with increased osteoblast numbers and osteoid surface. Marrow-derived colony forming unit-fibroblastic was reduced in DKO mice. Together our data suggest that when both TSP1 and TSP2 are absent, a unique bone phenotype not predicted by the single knockouts, is manifested

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Exacerbated neuronal ceroid lipofuscinosos phenotype in Cln1/5 double knock-out mice

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