skip to main content


Title: Developmental and degenerative cardiac defects in the Taiwanese mouse model of severe spinal muscular atrophy
Abstract

Spinal muscular atrophy (SMA), an autosomal recessive disease caused by a decrease in levels of the survival motor neuron (SMN) protein, is the most common genetic cause of infant mortality. Although neuromuscular pathology is the most severe feature ofSMA, other organs and tissues, including the heart, are also known to be affected in both patients and animal models. Here, we provide new insights into changes occurring in the heart, predominantly at pre‐ and early symptomatic ages, in the Taiwanese mouse model of severeSMA. Thinning of the interventricular septum and dilation of the ventricles occurred at pre‐ and early symptomatic ages. However, the left ventricular wall was significantly thinner inSMAmice from birth, occurring prior to any overt neuromuscular symptoms. Alterations in collagenIVprotein from birth indicated changes to the basement membrane and contributed to the abnormal arrangement of cardiomyocytes inSMAhearts. This raises the possibility that developmental defects, occurring prenatally, may contribute to cardiac pathology inSMA. In addition, cardiomyocytes inSMAhearts exhibited oxidative stress at pre‐symptomatic ages and increased apoptosis during early symptomatic stages of disease. Heart microvasculature was similarly decreased at an early symptomatic age, likely contributing to the oxidative stress and apoptosis phenotypes observed. Finally, an increased incidence of blood retention inSMAhearts post‐fixation suggests the likelihood of functional defects, resulting in blood pooling. These pathologies mirror dilated cardiomyopathy, with clear consequences for heart function that would likely contribute to potential heart failure. Our findings add significant additional experimental evidence in support of the requirement to develop systemic therapies forSMAcapable of treating non‐neuromuscular pathologies.

 
more » « less
NSF-PAR ID:
10066827
Author(s) / Creator(s):
 ;  ;  ;  ;  
Publisher / Repository:
Wiley-Blackwell
Date Published:
Journal Name:
Journal of Anatomy
Volume:
232
Issue:
6
ISSN:
0021-8782
Page Range / eLocation ID:
p. 965-978
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. Abstract  
    more » « less
  2. Background

    Premature restriction or closure of foramen ovale (FO) in otherwise structurally normal hearts may be associated with right ventricular dilation, tricuspid regurgitation, pericardial effusion, heart failure, even poor perinatal outcomes. Data about these rare conditions are lacking.

    Methods

    We retrospectively reviewed the echocardiographic records of 9704 fetuses seen from 2010 to 2014 in Beijing Anzhen Hospital, a regional and national referral center, to ascertain the presence of restriction or closure ofFO. We collected the fetal echocardiography and perinatal outcome data for this group of fetuses with restriction or closure ofFO.

    Results

    In this large, single‐institution cohort (n = 9704), 6707 fetuses seen between 23 and 37 weeks of gestation had normal heart structures; of these, 60 (0.89%) had restrictiveFO(rFO) and 5 (0.07%) had closure ofFO(cFO). Fetal echocardiographic images showed right atrial dilation in 48 (73.84%), right ventricular dilation in 38 (58.46%), tricuspid regurgitation in 19 (29.23%), and pericardial effusion in 10 (15.38%). Also in this group, 50 (83.3%) withrFOand 4 (80.0%) withcFOhad follow‐up data. No prenatal deaths occurred in either therFOor thecFOgroup, but the neonatal mortality included 1 in therFOgroup and 2 in thecFOgroup.

    Conclusion

    PrematurerFO/cFOare rare in fetuses with otherwise structurally normal hearts. The fetal echocardiographic characteristics include right atrial and ventricular dilated, tricuspid regurgitation, and pericardial effusion. Most fetuses had a good outcome, although there was an association betweenrFO, especiallycFO, with neonatal morality and complications (prematurity, maternal preeclampsia and placental abruption, hydrops fetalis, and necrotizing enterocolitis with perforation).

     
    more » « less
  3. Abstract

    Zinc is important in neurogenesis, but excessive levels can cause apoptosis and other pathologies leading to cognitive impairments. Mast cells are present in many brain regions including the hippocampus, an area rich in vesicular zinc. Mast cells contain zinc‐rich granules and a well‐developed mechanism for uptake of zinc ions; both features point to the potential for a role in zinc homeostasis. Prior work using the Timm stain supported this hypothesis, as increased labile zinc was detected in the hippocampus of mast cell‐deficient mice compared to wild‐type mice while no differences in total zinc were found between the two genotypes in the whole brain or other tissues. The current report further examines differences in zinc homeostasis between wild‐type and mast cell‐deficient mice by exploring the zinc transporter ZnT3, which transports labile zinc into synaptic vesicles. The first study used immunocytochemistry to localize ZnT3 within the mossy fibre layer of the hippocampus to determine whether there was differential expression of ZnT3 in wild‐type versus mast cell‐deficient mice. The second study used inductively coupled plasma mass spectrometry (ICPMS) to determine total zinc content in the whole dentate gyrus of the two genotypes. The immunocytochemical results indicate that there are higher levels of ZnT3 localized to the mossy fibre layer of the dentate gyrus of mast cell‐deficient mice than in wild‐type mice. TheICPMSdata reveal no differences in total zinc in dentate gyrus as a whole. The results are consistent with the hypothesis that mast cells participate in zinc homeostasis at the level of synaptic vesicles.

     
    more » « less
  4. Summary

    Catabolism of fatty acids stored in oil bodies is essential for seed germination and seedling development in Arabidopsis. This fatty acid breakdown occurs in peroxisomes, organelles that sequester oxidative reactions. Import of peroxisomal enzymes is facilitated by peroxins includingPEX5, a receptor that delivers cargo proteins from the cytosol to the peroxisomal matrix. After cargo delivery, a complex of thePEX1 andPEX6ATPases and thePEX26 tail‐anchored membrane protein removes ubiquitinatedPEX5 from the peroxisomal membrane. We identified Arabidopsispex6andpex26mutants by screening for inefficient seedling β‐oxidation phenotypes. The mutants displayed distinct defects in growth, response to a peroxisomally metabolized auxin precursor, and peroxisomal protein import. The lowPEX5 levels in these mutants were increased by treatment with a proteasome inhibitor or by combiningpex26with peroxisome‐associated ubiquitination machinery mutants, suggesting that ubiquitinatedPEX5 is degraded by the proteasome when the function ofPEX6 orPEX26 is reduced. Combiningpex26with mutations that increasePEX5 levels either worsened or improvedpex26physiological and molecular defects, depending on the introduced lesion. Moreover, elevatingPEX5 levels via a35S:PEX5transgene exacerbatedpex26defects and ameliorated the defects of only a subset ofpex6alleles, implying that decreasedPEX5 is not the sole molecular deficiency in these mutants. We found peroxisomes clustered around persisting oil bodies inpex6andpex26seedlings, suggesting a role for peroxisomal retrotranslocation machinery in oil body utilization. The disparate phenotypes of thesepexalleles may reflect unanticipated functions of the peroxisomalATPase complex.

     
    more » « less
  5. Summary

    Signalling events downstream the B‐cell receptor (BCR) are central for the survival and progression of chronic lymphocytic leukaemia (CLL) cells. Focal adhesion kinase (FAK), regulated through calpain, interacts with molecules ofBCRsignalling, cytoskeletal modelling and disease progression, such as Src/Lyn, cortactin andHS1. Hypothesizing thatFAKmight play a key role inCLLpathogenesis, we observed a down‐modulation ofFAKwhole form, associated withFAKcleavage due to calpain activity uponBCRstimulation. Patients, whose cells were able to release Ca++afterBCRstimulation, had less amount of full‐lengthFAK, which translated into a higher presence of cleaved/activated form of the protein phosphorylated atY397, these features being mostly shown by immunoglobulin heavy chain (IGHV)‐unmutated poor‐prognosis patients. Moreover, we found that cortactin andHS1proteins were overexpressed in those cells, suggesting a possible interplay withFAK. Treatment with theFAKinhibitor Defactinib was able to induce apoptosis inCLLcells. In conclusion, the malignant phenotype in unfavourable‐prognosis patients seems to be encouraged by the overexpression of cortactin andHS1, that, together withFAK, may be involved in a druggable pathogenetic pathway inCLL.

     
    more » « less