Widespread tissue hypoxia dysregulates cell and metabolic pathways

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Neurodegenerative diseases are also vascular diseases. This has long been observe in Alzheimer, but it is also true for amyotrophic lateral sclerosis or multiple sclerosis. The purpose of this study by Elena Hernandez-Gerez and al was to determine the extent and role of systemic hypoxia in the pathogenesis of spinal muscular atrophy (SMA).

Necrosis at the tip of toes and fingers has been observed in SMA patients, as well as thrombotic occlusions of small vessels, together with significant reductions in vascular density in the mouse models of severe SMA, these symptoms suggest defects in blood supply. In fact SMA mouse spinal cord is hypoxic, suggesting that other tissues may also be affected. All tissues can be damaged by hypoxia, but motor neurons are particularly sensitive.

enter image description here Source: James Heilman, MD via Wikipedia

Historically, non-neuronal pathology has been of less interest, as the severe motor neuron pathology negated the need to consider additional therapies.

However, now that treatments have become available, including Nusinersen (Spinraza) and Onasemnogene abeparvovec (Zolgensma), survival is increasing, but so is the likelihood of significant non-neuronal co-morbidities. It is now clear that a number of non-neuronal tissues also show disease-related pathology, and that the cardiovascular system is particularly involved, with heart, vessels, and circulating cells all described as pathological in severe mouse models and now also increasingly in patients.

The authors were keen to understand the extent to which vascular dysfunction could contribute to and potentially exacerbate motor neuron death, having previously shown decreased vasculature associated with tissue hypoxia in spinal cord. Hypoxia was assayed in vivo in early-symptomatic (postnatal day 5) SMA-model mice.

Hypoxia is widespread in neuronal and nonneuronal tissues in pre/early-symptomatic SMA mice Here the authors show using qualitative and quantitative techniques that a wide range of tissues from brain and eye, through skeletal muscle to visceral organs are significantly hypoxic at pre/ early symptomatic time points. Importantly skin and lung, which can absorb atmospheric oxygen, showed no evidence of hypoxia.

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. This immediately suggests a need to assess SMA patients, and particularly those undergoing therapy, for ongoing, perhaps low-level chronic hypoxia, and also potential utilization of oxygenation as an easy to deliver, ameliorative, therapy.


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