Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin-induced cell death

Wang, Wenlan; DiMatteo, Darlise; Funanage, Vicky L.; Scavina, Mena

doi:10.1016/j.ymgme.2004.12.015

Cited by 14 publications

(29 citation statements)

References 33 publications

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“…In characterising a PI3-kinase/Akt inhibition apoptotic cell death model using differentiated SH-SY5Y human neuronal-like cells, we demonstrated that SMN protein over-expression reduces caspase-3 activation by preventing calpain mediated cleavage of the caspase-3 prodomain (Wolf et al, 1999). Our data thus supports and extends previous findings that SMN plays a role in modulating apoptosis and reducing caspase-3 activity (Kerr et al, 2000;Vyas et al, 2002;Wang et al, 2005;Parker et al, 2008).…”

Section: Discussionsupporting

confidence: 92%

“…In our model, glutamate exposure causes calpain activation without caspase-3 activation (Meade et al, 2009). The lack of protection seen in the excitotoxic model is consistent with the notion that SMN can only protect against caspase-3 dependent apoptosis (Vyas et al, 2002;Wang et al, 2005;Parker et al, 2008).…”

Section: Discussionsupporting

confidence: 83%

“…Over-expression of SMN protein protects cells against nerve growth factor deprivation in rat PC12 cells, camptothecin induced apoptosis in human SMA patient fibroblasts and staurosporine induced death in mouse NSC34 cells (Vyas et al, 2002;Wang et al, 2005;Parker et at., 2008). In this study, adenoviral vectors were used to investigate the survival mechanisms of the SMN protein in both apoptotic and oxidative models in differentiated human SH-SY5Y neuroblastoma cells, and in an excitotoxic model in rat cortical neurons.…”

Section: Introductionmentioning

confidence: 99%

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Survival of motor neuron protein over-expression prevents calpain-mediated cleavage and activation of procaspase-3 in differentiated human SH-SY5Y cells

et al. 2011

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. cultures over-expressing SMN harvested pre-and post-Akt/PI3-kinase inhibition indicated that SMN protein inhibited caspase-3 activation via blockade of calpain mediated procaspase-3 cleavage. This study has revealed a novel anti-apoptotic function for the SMN protein in differentiated SH-SY5Y cells. Finally, the cell death model described herein will allow the assessment of future therapeutic agents or strategies aimed at increasing SMN protein levels.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

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Survival of motor neuron protein over-expression prevents calpain-mediated cleavage and activation of procaspase-3 in differentiated human SH-SY5Y cells

et al. 2011

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“…This hypothesis was based on the evidence that SMN and some of its binding partners function in DNA repair (17,18) and that human SMA fibroblasts show increased sensitivity to the DNA topoisomerase-I inhibitor camptothecin (78), which induces DNA-SSBs and apoptosis (51). Moreover, our experiments demonstrating DNA damage accumulation in SMA mouse skeletal muscles very early in the disease suggested that muscle-specific DNA damage repair defects could be a pathological mechanism in SMA (14).…”

Section: Fayzullina Andmentioning

confidence: 84%

DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy

Fayzullina

Martin

2016

J Neuropathol Exp Neurol

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We studied DNA damage response (DDR) and DNA repair capacities of skeletal muscle cells from a mouse model of infantile spinal muscular atrophy (SMA) caused by loss-of-function mutation of survival of motor neuron (Smn). Primary myocyte cultures derived from skeletal muscle satellite cells of neonatal control and mutant SMN mice had similar myotube length, myonuclei, satellite cell marker Pax7 and differentiated myotube marker myosin, and acetylcholine receptor clustering. DNA damage was induced in differentiated skeletal myotubes by c-irradiation, etoposide, and methyl methanesulfonate (MMS). Unexposed control and SMA myotubes had stable genome integrity. After c-irradiation and etoposide, myotubes repaired most DNA damage equally. Control and mutant myotubes exposed to MMS exhibited equivalent DNA damage without repair. Control and SMA myotube nuclei contained DDR proteins phosphop53 and phospho-H2AX foci that, with DNA damage, dispersed and then re-formed similarly after recovery. We conclude that mouse primary satellite cell-derived myotubes effectively respond to and repair DNA strand-breaks, while DNA alkylation repair is underrepresented. Morphological differentiation, genome stability, genome sensor, and DNA strand-break repair potential are preserved in mouse SMA myocytes; thus, reduced SMN does not interfere with myocyte differentiation, genome integrity, and DNA repair, and faulty DNA repair is unlikely pathogenic in SMA.

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“…It seems that apoptosis is inappropriately prolonged [3,38,42,65,70,75,84,92], because during the midgestational period this is the normal process by which 40-70% of the embryonic motor neurons in the spinal cord undergo naturally occurring programmed cell death immediately following the arrival of their axons in muscle cells [16,62,90]. (10) In the end-stage of the disease, all apoptotic, heterotopic and chromatolytic neurons [27] eventually die.…”

Section: Neuropathological Changes In Sma and Proposed Pathogenetic Mmentioning

confidence: 99%

Pathogenesis of proximal autosomal recessive spinal muscular atrophy

Šimić

2008

Acta Neuropathol

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Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased levels of the SMN protein in subjects with proximal autosomal recessive spinal muscular atrophy (SMA), the exact sequence of pathological events leading to selective motoneuron cell death is not fully understood yet. In this review, new findings regarding the dual cellular role of the SMN protein (translocation of β-actin to axonal growth cones and snRNP biogenesis/pre-mRNA splicing) were integrated with recent data obtained by detailed neuropathological examination of SMA and control subjects. A presumptive series of 10 pathogenetic events for SMA is proposed as follows: (1) deletions or mutations of the SMN1 gene, (2) increased SMN mRNA decay and reduction in full-length functional SMN protein, (3) impaired motoneuron axonoand dendrogenesis, (4) failure of motoneurons to form synapses with corticospinal fibers from upper motoneurons, (5) abnormal motoneuron migration towards ventral spinal roots, (6) inappropriate persistence of motoneuron apoptosis due to impaired differentiation and motoneuron displacement, (7) substantial numbers of motoneurons continuing to migrate abnormally ("heterotopic motoneurons") and entering into the ventral roots, (8) attracted glial cells following these heterotopic motoneurons, which form the glial bundles of ventral roots, (9) impaired axonal transport of actin, causing remaining motoneurons to become chromatolytic, and (10) eventual death of all apoptotic, heterotopic and chromatolytic neurons, with apoptosis being more rapid and predominating in the earlier stages, with death of heterotopic and chromatolytic neurons occurring more slowly by necrosis during the later stages of SMA. According to this model, the motoneuron axonopathy is more important for pathogenesis than the ubiquitous nuclear splicing deficit. It is also supposed that individually variable levels of SMN protein, together with influences of other phenotype modifier genes and their products, cause the clinical SMA spectrum through differential degree of motoneuron functional loss.

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Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin-induced cell death

Cited by 14 publications

References 33 publications

Survival of motor neuron protein over-expression prevents calpain-mediated cleavage and activation of procaspase-3 in differentiated human SH-SY5Y cells

Survival of motor neuron protein over-expression prevents calpain-mediated cleavage and activation of procaspase-3 in differentiated human SH-SY5Y cells

DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy

Pathogenesis of proximal autosomal recessive spinal muscular atrophy

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