Cerebral dopamine neurotrophic factor and its functional fragments induce calcium signal through sigma-1 receptor and protect neurons against glutamate-induced excitotoxicity Nafisa Komilova, Noemi Esteras, Alessandra Preziuso, Lauren Millichap, Ausra Domanska, Anastasia Ludwig, Natalia Kulesskaya, Henri J. Huttunen, Kira M. Holmström, Andrey Y. Abramov, Plamena R. Angelova Biomedicine and Pharmacotherapy, 2026 Cerebral Dopamine Neurotrophic Factor (CDNF) is known to protect neurons in various pathologies. HER-096 is a CDNF-derived brain-penetrating peptidomimetic which also possesses neuroprotective properties. However, the mechanism underlying the cytoprotective effects is not fully understood. Using primary cortical co-culture of neurons and astrocytes we have found that both CDNF and HER-096 can induce intracellular calcium signals predominantly in astrocytes by release of Ca 2 + from endoplasmic reticulum to cytosol. This decrease in the ER Ca 2+ pool activates store-operated calcium entrance (SOCE). Initial Ca 2+ signal in these cells could be inhibited by the sigma-1 receptor antagonist BD-1047. CDNF and HER-096 reduced the glutamate-induced delayed Ca 2+ deregulation and mitochondrial depolarisation which leads to significant protection against glutamate-induced excitotoxicity. Thus, the CDNF and HER-096 sigma-1 receptor mediated Ca 2+ signal in astrocytes and neurons, from the ER, could modify the effects of high concentrations of glutamate that lead to neuroprotection. • Both CDNF and HER-096 can induce intracellular calcium signals predominantly in astrocytes by ER Ca 2+ release to cytosol. • This decrease in the ER Ca 2+ pool activates store-operated calcium entrance (SOCE). • Initial Ca 2+ signal induced by CDNF and HER-096 is sigma-1-receptor-mediated. • CDNF and HER-096 exhibit protection against glutamate-induced excitotoxicity in neurons.
Charcot Marie Tooth disease pathology is associated with mitochondrial dysfunction and lower glutathione production Nafisa R. Komilova, Plamena R. Angelova, Elisa Cali, Annarita Scardamaglia, Ulugbek Z. Mirkhodjaev, Henry Houlden, Noemi Esteras, Andrey Y. Abramov Cellular and Molecular Life Sciences, 2025 Charcot Marie Tooth (CMT) or hereditary motor and sensory neuropathy is a heterogeneous neurological disorder leading to nerve damage and muscle weakness. Although multiple mutations associated with CMT were identified, the cellular and molecular mechanisms of this pathology are still unclear, although most of the subtype of this disease involve mitochondrial dysfunction and oxidative stress in the mechanism of pathology. Using patients’ fibroblasts of autosomal recessive, predominantly demyelinating form of CMT—CMT4B3 subtype, we studied the effect of these mutations on mitochondrial metabolism and redox balance. We have found that CMT4B3-associated mutations decrease mitochondrial membrane potential and mitochondrial NADH redox index suggesting an increase rate of mitochondrial respiration in these cells. However, mitochondrial dysfunction had no profound effect on the overall levels of ATP and on the energy capacity of these cells. Although the rate of reactive oxygen species production in mitochondria and cytosol in fibroblasts with CMT4B3 pathology was not significantly higher than in control, the level of GSH was significantly lower. Lower level of glutathione was most likely induced by the lower level of NADPH production, which was used for a GSH cycling, however, expression levels and activity of the major NADPH producing enzyme Glucose-6-Phosphate Dehydrogenase (G6PDH) was not altered. Low level of GSH renders the fibroblast with CMT4B3 pathology more sensitive to oxidative stress and further treatment of cells with hydroperoxide increases CMT patients’ fibroblast death rates compared to control. Thus, CMT4B3 pathology makes cells vulnerable to oxidative stress due to the lack of major endogenous antioxidant GSH.
Molecule Formation Energy and Atomic Charge Effectiveness of Membrane-Active Diacyl Derivatives of Dibenzo-18-Crown-6 Biointerface Research in Applied Chemistry, 2024 In this study, we present an investigation into the impact of substituent length within the benzene ring of diacyl derivatives of dibenzo-18-crown-6 (DB18C6) on the charges exhibited by oxygen atoms in the macrocycle. Our analysis reveals that the oxygens located at positions 1 and 4 of the nearest pyrocatechol group, situated at a separation of two carbon atoms from the benzene ring substituent, exhibit only minimal changes in charge when compared to oxygens located at positions 3 and 6, located at three carbon atoms. These may indicate that "sandwich" structures form during complex formation. Our research has revealed a correlation between the molecule formation energy of diacyl derivatives of DB18C6 and the enthalpy (ΔH) of complex formation. Specifically, the PM3 method was utilized to calculate the molecule formation energy, which showed an increase in energy from 4',4"-diacetyl-DB18C6 to 4',4"(5")-divaleryl-DB18C6. Similarly, data obtained from the MM+ technique demonstrated a rise in molecule formation energy from 4',4"-diacetyl DB18C6 to 4',4"(5")-divaleryl-DB18C6, and in both cases, this value remained at a close level achieved for 4',4"(5")-divaleryl-DB18C6. Specifically, we observed a gradual increase in molecule formation energy from 4',4"-diacetyl-DB18C6 to 4',4"(5")-divaleryl-DB18C6, which was consistent with the corresponding increase in ΔH and Ca2+ ionophore activity.
Stability of Structure, Chemical Properties, and Biological Effects of Diacyl Derivatives of Dibenzo-18-crown-6 Biointerface Research in Applied Chemistry, 2024 The interplay between Ca2+ ions and neuronal dysfunction has recently gained significant attention. A growing body of evidence implicates Ca2+ in the pathophysiology of neurodegenerative disorders, including Parkinson's disease. The rate of protein aggregate formation, mitophagy, and autophagy abnormalities in Parkinson's disease may be influenced by Ca2+ ions, and specific ionophores have been used to study this phenomenon. We investigated the potential of diacyl derivatives of dibenzo-18-crown-6 (DB18C6), namely 4′,4′′(5′′)-dibutyryl-DB18C6 and 4′,4′′(5′′)-divaleryl-DB18C6 and 4′,4′′-diacetyl-DB18C6 as an alternative to these specific ionophores. Our study provides evidence that both 4′,4′′(5′′)-dibutyryl-DB18C6 and 4′,4′′(5′′)-divaleryl-DB18C6 can effectively promote Ca2+ transport across fibroblast cell membranes at 10 and 100 nanomolar concentrations. Notably, the studied crown ethers do not appear to impact intracellular pH or mitochondrial membrane potential. Also, we assessed these molecules' structural stability and chemical purity, confirming their integrity and suitability for future research. These results suggest that using crown ethers as ionophores may be a promising alternative to specific ionophores in studying the impact of Ca2+ ions on various cellular processes in Parkinson's disease.
Metabolically induced intracellular pH changes activate mitophagy, autophagy, and cell protection in familial forms of Parkinson's disease Nafisa R. Komilova, Plamena R. Angelova, Alexey V. Berezhnov, Olga A. Stelmashchuk, Ulugbek Z. Mirkhodjaev, Henry Houlden, Alexander V. Gourine, Noemi Esteras, Andrey Y. Abramov FEBS Journal, 2022 Parkinson's disease (PD) is a progressive neurodegenerative disorder induced by the loss of dopaminergic neurons in midbrain. The mechanism of neurodegeneration is associated with aggregation of misfolded proteins, oxidative stress, and mitochondrial dysfunction. Considering this, the process of removal of unwanted organelles or proteins by autophagy is vitally important in neurons, and activation of these processes could be protective in PD. Short‐time acidification of the cytosol can activate mitophagy and autophagy. Here, we used sodium pyruvate and sodium lactate to induce changes in intracellular pH in human fibroblasts with PD mutations (Pink1, Pink1/Park2, α‐synuclein triplication, A53T). We have found that both lactate and pyruvate in millimolar concentrations can induce a short‐time acidification of the cytosol in these cells. This induced activation of mitophagy and autophagy in control and PD fibroblasts and protected against cell death. Importantly, application of lactate to acute brain slices of WT and Pink1 KO mice also induced a reduction of pH in neurons and astrocytes that increased the level of mitophagy. Thus, acidification of the cytosol by compounds, which play an important role in cell metabolism, can also activate mitophagy and autophagy and protect cells in the familial form of PD.
