Can neuronal degeneration be delayed by activation of a cold shock protein ?

Therapeutic hypothermia is used in some clinics for neuroprotection, for example, in hypoxic-ischemic brain damage of newborns or after head injuries, strokes, and adult heart surgery. Here, the measurement of a biomarker (RBM3) is used to monitor therapeutic success. RBM3 is an RNA-binding protein whose gene is activated when body temperature drops below a certain level (e.g., in marmots during hibernation). The brain then goes into a month-long energy-saving mode and is apparently protected via RBM3, which is therefore also known as a cold shock protein.

Since induced cooling in humans requires intensive care and has a not insignificant risk of blood clots, pneumonia and other complications, inducing RBM3 without hypothermia could provide an alternative neuroprotective treatment that might be applicable to Alzheimer's disease and other neurodegenerative disorders.

A research group led by biochemist Florian Heyd of the Institute of Chemistry and Biochemistry at Freie Universität Berlin has now developed a molecular biological method to turn on the RBM3 gene. Together with neuroscientists at the University of Cambridge, the biochemists investigated the role of RBM3 in young mice that produce harmful proteins (known as prions) in the brain and subsequently develop neurodegeneration similar to Creutzfeldt-Jakob disease. If these animals are temporarily cooled, they are later protected from the prions for many weeks at normal body temperature. In contrast, neurodegeneration was enhanced in animals not expressing RBM3.

In further experiments, they used genetic manipulation to get the mice to produce the cold shock protein at normal body temperature. This also delayed prion disease. To elicit the beneficial effect of lower body temperature without lowering body temperature, the authors developed a method, recently published in EMBO Molecular Medicine, to turn on the RBM3 gene. This involves injecting a specific antisense oligonucleotide (ASO) that interferes with the genetic regulation of the RBM3 gene and only needs to be given once to produce a long-term beneficial effect (by regulating so-called RNA splicing, which I described in my blog post of 07/20/2013).

ASOs have been successfully applied to children with spinal muscular atrophy and have also been approved for the treatment of rapidly progressive amyotrophic lateral sclerosis (ALS). However, they can be recognized by the immune system as foreign and trigger a violent defense reaction. Therefore, before RBM3-inducing ASOs can be tested in humans, further animal experiments and safety studies would need to be conducted.

Reference:

Preußner M, Smith HL, Hughes D, ..., Mallucci GR, Heyd F (2023) ASO targeting RBM3 temperature-controlled poison exon splicing prevents neurodegeneration in vivo. EMBO Mol Med 15: e17157

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