Inhibition of transient receptor potential melastatin 7 (TRPM7) protects against Schwann cell trans-dedifferentiation and proliferation during Wallerian degeneration

Abstract

Irreversible peripheral neurodegenerative diseases such as diabetic peripheral neuropathy are becoming increasingly common due to rising rates of diabetes mellitus; however, no effective therapeutic treatments have been developed. One of main causes of irreversible peripheral neurodegenerative diseases is dysfunction in Schwann cells, which are neuroglia unique to the peripheral nervous system (PNS). Because homeostasis of calcium (Ca 2+) and magnesium (Mg 2+) is essential for Schwann cell dynamics, the regulation of these cations is important for controlling peripheral nerve degeneration and regeneration. Transient receptor potential melastatin 7 (TRPM7) is a non-selective ion (Ca 2+ and Mg 2+) channel that is expressed in Schwann cells. In the present study, we demonstrated in an ex vivo culture system that inhibition of TRPM7 during peripheral nerve degeneration (Wallerian degeneration) suppressed dedifferentiable or degenerative features (trans-dedifferentiation and proliferation) and conserved a differentiable feature of Schwann cells. Our results indicate that TRPM7 could be very useful as a molecular target for irreversible peripheral neurodegenerative diseases, facilitating discovery of new therapeutic methods for improving human health.

Piezo channels contribute to the regulation of myelination in Schwann cells

“…Though it is unknown if all TRP channels are expressed in peripheral nerves and Schwann cells, several TRP channels have been shown to affect peripheral nerve repair. TRPV4 and TRPM7 regulate Schwann cell dedifferentiation following nerve injury, as ablation of either TRPV4 or TRPM7 in mouse Schwann cells impaired the demyelinating process, resulting in delayed remyelination and functional recovery of sciatic nerves (Feng et al, 2020; Kim, Lee, et al, 2020). In addition, TRPA1 mediates neuroinflammation following nerve ligation, as silencing of TRPA1 in mouse Schwann cells limited the recruitment of macrophages and allodynia (De Logu et al, 2017).…”

Novel Cinnamaldehyde Derivatives Inhibit Peripheral Nerve Degeneration by Targeting Schwann Cells

“…TRPA1 is also involved in macrophage infiltration, which increases neuroinflammation and myelin engulfment during PND [ 14 , 15 ]. Furthermore, because TRP melastatin 7 (TRPM7), like other TRP families, is also known to inhibit PND [ 25 ], TRPA1 may have the potential as a therapeutic target in Schwann cells for PND. To select one compound for further evaluation, we set up molecular docking between 3a – 3l and TRPA1 as a filter to reduce the candidates and evaluated their binding affinity compared to that of CAH as the control because CAH is a potential TRPA1 ligand [ 26 , 27 ].…”

Syncytin, envelope protein of human endogenous retrovirus (HERV): no longer ‘fossil’ in human genome

“…SZ patients and patients with other neurological disorders such as Alzheimer's disease display calcium imbalance (Berridge 2012 ). Syncytin-1 induces Ca 2+ influx in human neuroblastoma cells and upregulates the expression of transient receptor potential channel C3 (TRPC3) via directly regulating its expression or downregulating disrupted-in-schizophrenia 1 (DISC1), a susceptibility factor for SZ, which is a scaffold protein interacting with various proteins to regulate synaptic processes and dopamine signaling (Chen et al 2019 ; Kim et al 2020 ).…”