Research Roundup Neuroscience

What causes drug resistance in epileptic patients?

Epilepsy is one of the primary neurological diseases and affects over 50 million people worldwide. Unfortunately, despite the continuing discoveries of new anticonvulsant drugs, 30% of all epileptic patients are drug-resistant.

Drug-resistant epilepsy (DRE or refractory epilepsy) is a term used to describe when anti-epileptic drugs have failed to control seizures. 

Several mechanisms have been hypothesized to explain the processes occurring in the epileptogenic brain zones of DRE patients, including cellular death associated with high numbers of tetraploid neurons and astrocytes, as reported in a new study by Sanz-García et al. (2022).

Results show that the percentage of tetraploid astrocytes (NDRG2-positive) was higher in epilepsy patients' hippocampus than in the controls. Interestingly, no differences were found in NDRG2-labeled tetraploid astrocytes in other epileptogenic zones such as the cortex and amygdala, compared to the controls.

This study has changed our understanding of the causes of DRE by showing that tetraploid neurons and astrocytes are significantly increased in DRE, more precisely in the temporal lobe epilepsy involving the hippocampal region of the brain. So, understanding the role of these cells in the pathogenesis of epilepsy could pave the way to new treatment lines for DRE patients.

The Anti-NDRG2 antibody HPA002896 (Atlas Antibodies) was used in the study for the tetraploidy analysis as a marker protein of differentiated astrocytes. 

Reference

Sanz-García et al. (2022) Neuronal and astrocytic tetraploidy is increased in drug-resistant epilepsy.

 

A newly discovered and evolutionarily conserved feature of oligodendrocytes.

The central function of oligodendrocytes is to generate myelin, which is the membrane that wraps tightly around axons. Myelin enables the rapid conduction of action potentials within the constrained space of the CNS.

The study of myelin has recently been reinvigorated by the ability to fluorescently label oligodendrocytes, myelin components, and recipient axons, allowing the dynamics of myelination to be described with high temporal and spatial resolution in vivo.

It is known that the distinct myelin patterns across brain regions and neuron types are established as newly generated oligodendrocytes form multilamellar membrane sheaths around a cohort of nearby axons. However, the mechanisms that control the positioning of myelin along individual axons remain to be defined.

By providing new insights into the development of myelinated sheaths, a study by Call et al. (2022) reveals a previously undescribed and evolutionarily conserved feature of oligodendrocytes involving internodes and oligodendrogenesis-independent mechanisms.

Results show a distinct mode of myelination (conserved between zebrafish, mouse, and human) in which oligodendrocytes form thin extensions of myelin sheaths that cross nodes of Ranvier and are called paranodal bridges. 

Image from Call et al. (2022)

The Anti-CNP monoclonal antibody AMAb91072 (Atlas Antibodies) was used in the study as a marker protein of paranodal bridges.

Reference

Call et al. (2022) Oligodendrocytes form paranodal bridges that generate chains of myelin sheaths that are vulnerable to degeneration with age.

 

Additional References

Anti-NDRG2 (HPA002896)

Kronschläger MT, et al. (2021) Lamina‐specific properties of spinal astrocytes. Glia, 69(7):1749-1766

Mir BA, et al. (2019) MicroRNA suppression of stress-responsive NDRG2 during dexamethasone treatment in skeletal muscle cells. BMC Mol Cell Biol, 20:12

Kloten V, et al. (2016) Abundant NDRG2 expression Is associated with aggressiveness and unfavorable patients' outcome in basal-like breast cancer. PLoS One, 11(7):e0159073  

Anderson KJ,  et al. (2015) NDRG2 promotes myoblast proliferation and caspase 3/7 activities during differentiation, and attenuates hydrogen peroxide – but not palmitate-induced toxicity. FEBS Open Bio, 5:668-681

Stadler C,  et al. (2013) Immunofluorescence and fluorescent-protein tagging show high correlation for protein localization in mammalian cells. Nat Methods, 10(4):315-23

Schilling SH, et al. (2009) NDRG4 is required for cell cycle progression and survival in glioblastoma cells. J Biol Chem, 284(37):25160-25169

Mulder J,  et al. (2009) Tissue profiling of the mammalian central nervous system using human antibody-based proteomics. Mol Cell Proteomics, 8(7):1612-1622

Tepel M,  et al. (2008) Frequent promoter hypermethylation and transcriptional downregulation of the NDRG2 gene at 14q11.2 in primary glioblastoma. Int J Cancer, 123(9):2080-6

Anti-CNP (AMAb91072)

Swire M, et al. (2021) Oligodendrocyte HCN2 channels regulate myelin sheath length. J Neurosci, 41(38):7954-7964

James OG, et al. (2021) iPSC-derived myelinoids to study myelin biology of humans. Dev Cell, 56(9):1346-1358.e6

Swire M,  et al. (2019) Endothelin signaling mediates experience-dependent myelination in the CNS. eLife, 8:e49493

Milbreta U, et al. (2018) Scaffold-mediated sustained, non-viral delivery of miR-219/miR-338 promotes CNS remyelination. Mol Ther, 27(2):411-423

 

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