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  • Widespread tissue hypoxia dysregulates cell and metabolic pathways in SMA.

Widespread tissue hypoxia dysregulates cell and metabolic pathways in SMA.

Annals of clinical and translational neurology (2020-08-14)
Elena Hernandez-Gerez, Sergio Dall'Angelo, Jon M Collinson, Ian N Fleming, Simon H Parson
ABSTRACT

The purpose of the study was to determine the extent and role of systemic hypoxia in the pathogenesis of spinal muscular atrophy (SMA). Hypoxia was assayed in vivo in early-symptomatic (postnatal day 5) SMA-model mice by pimonidazole and [18 F]-Fluoroazomycin arabinoside injections, which accumulate in hypoxic cells, followed by immunohistochemistry and tracer biodistribution evaluation. Glucose uptake in hypoxic cells was assayed by [18 F]-Fluorodeoxyglucose labeling. In vitro knockdown of Survival Motor Neuron (SMN) was performed on motor neurons and lactate metabolism measured biochemically, whereas cell cycle progression and cell death were assayed by flow cytometry. All assays found significant levels of hypoxia in multiple organ systems in early symptomatic SMA mouse pups, except aerated tissues such as skin and lungs. This was accompanied by significantly increased glucose uptake in many affected organs, consistent with a metabolic hypoxia response. SMN protein levels were shown to vary widely between motor neuron precursors in vitro, and those with lower levels were most susceptible to cell death. In addition, SMA-model motor neurons were particularly sensitive to hypoxia, with reduced ability to transport lactate out of the cell in hypoxic culture, and a failure in normal cell cycle progression. Not only is there widespread tissue hypoxia and multi-organ cellular hypoxic response in SMA model mice, but SMA-model motor neurons are especially susceptible to that hypoxia. The data support the hypothesis that vascular defects leading to hypoxia are a significant contributor to disease progression in SMA, and offer a route for combinatorial, non-SMN related therapy.

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Sigma-Aldrich
Protease Inhibitor Cocktail, for use with mammalian cell and tissue extracts, DMSO solution
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A583113-100MG100 mg
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$39.10
A583113-250MG250 mg
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$66.70
A583113-1G1 g
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Sigma-Aldrich
Anti-SMN Antibody, clone 2B1, clone 2B1, from mouse
Sign Into View Organizational & Contract Pricing
SKUVendor SKUPack SizeAvailabilityPrice
A583113-100MG100 mg
Ships in 7 days - from Aldrich Partner.
$39.10
A583113-250MG250 mg
Ships in 7 days - from Aldrich Partner.
$66.70
A583113-1G1 g
Ships in 7 days - from Aldrich Partner.
$121.90

To order products, please contact your local dealer.