Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration

Jiang D, Li T, Guo C, Tang TS, Liu H. Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration. Cell & Bioscience. 2023 Jan;13(1):10. DOI: 10.1186/s13578-023-00953-4. PMID: 36647159; PMCID: PMC9841685. 

This review first gives an overview of the regulatory mechanisms of chromatin remodeling. We then focus mainly on discussing the physiological functions of chromatin remodeling, particularly histone and DNA modifications and the four classes of ATP-dependent chromatin-remodeling enzymes, in the central and peripheral nervous systems under healthy and pathological conditions, that is, in neurodegenerative disorders. Finally, we provide an update on the development of potent and selective small molecule modulators targeting various chromatin-modifying proteins commonly associated with neurodegenerative diseases and their potential clinical applications.

Leveraging Computational Intelligence Techniques for Diagnosing Degenerative Nerve Diseases: A Comprehensive Review, Open Challenges, and Future Research Directions

Bhachawat S, Shriram E, Srinivasan K, Hu YC. Leveraging Computational Intelligence Techniques for Diagnosing Degenerative Nerve Diseases: A Comprehensive Review, Open Challenges, and Future Research Directions. Diagnostics (Basel, Switzerland). 2023 Jan;13(2):288. DOI: 10.3390/diagnostics13020288. PMID: 36673100; PMCID: PMC9858227. 

 Negenerative nerve diseases have been a popular topic of interest for a very long time. These disorders are untreatable and worsen the patient’s condition with time. The only measure we can currently take is to slow down the progression of these diseases. The early diagnosis of these diseases can enable patients to practice preventive measures before the disease progresses to an uncontrollable stage; hence, the early diagnosis and progression tracking of these disorders are crucial. Through this paper, we assessed the role of machine learning and deep learning in the diagnosis of these disorders and identified various algorithms that have shown promising results when used for the diagnosis of degenerative nerve diseases.

Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency

Sayles, N. M., Napierala, J. S., Anrather, J., Diedhiou, N., Li, J., Napierala, M., Puccio, H., & Manfredi, G. (2023). Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency. bioRxiv; doi:10.1101/2023.02.03.526305 

Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FxnG127V hearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has extremely low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.

Synaptic activity regulates mitochondrial iron metabolism to enhance neuronal bioenergetics

Tena-Morraja, P., Riqué-Pujol, G., Müller-Sánchez, C., Reina, M., Martínez-Estrada, O. M., & Soriano, F. X. (2023). Synaptic activity regulates mitochondrial iron metabolism to enhance neuronal bioenergetics. International Journal of Molecular Sciences, 24(2), 922. doi:10.3390/ijms24020922 

 We show that an episode of synaptic activity increases mitochondrial bioenergetics beyond the duration of the synaptic activity by transcriptionally inducing the expression of iron metabolism genes with the consequent enhancement of cellular and mitochondrial iron uptake. Iron is a necessary component of the electron transport chain complexes, and its chelation or knockdown of mitochondrial iron transporter Mfrn1 blocks the activity-mediated bioenergetics boost. We found that Mfrn1 expression is regulated by the well-known regulator of synaptic plasticity CREB, suggesting the coordinated expression of synaptic plasticity programs with those required to meet the associated increase in energetic demands

Redox sensitive human mitochondrial aconitase and its interaction with frataxin: In vitro and in silico studies confirm that it takes two to tango

Mansilla, S., Tórtora, V., Pignataro, F., Sastre, S., Castro, I., Chiribao, M. L., Robello, C., Zeida, A., Santos, J., & Castro, L. (2023). Redox sensitive human mitochondrial aconitase and its interaction with frataxin: In vitro and in silico studies confirm that it takes two to tango. Free radical biology & medicine, S0891-5849(23)00049-7. Advance online publication. doi:10.1016/j.freeradbiomed.2023.01.028 

 Multimer modeling and protein-protein docking predicted an ACO2-FXN complex where the metal ion binding region of FXN approaches the [3Fe-4S]+ cluster, supporting that FXN is a partner for reactivation of ACO2 upon oxidative cluster inactivation.

Brain-protective mechanisms of autophagy associated circRNAs: Kick starting self-cleaning mode in brain cells via circRNAs as a potential therapeutic approach for neurodegenerative diseases

Basri, R., Awan, F. M., Yang, B. B., Awan, U. A., Obaid, A., Naz, A., Ikram, A., Khan, S., Haq, I. U., Khan, S. N., & Aqeel, M. B. (2023). Brain-protective mechanisms of autophagy associated circRNAs: Kick starting self-cleaning mode in brain cells via circRNAs as a potential therapeutic approach for neurodegenerative diseases. Frontiers in molecular neuroscience, 15, 1078441. doi:10.3389/fnmol.2022.1078441

 

n this review, we aimed to summarize the latest studies on the role of brain-protective mechanisms of autophagy associated circRNAs in neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease, Huntington's disease, Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and Friedreich's ataxia) and how this knowledge can be leveraged for the development of novel therapeutics against them. Autophagy stimulation might be potential one-size-fits-all therapy for neurodegenerative disease as per considerable body of evidence, therefore future research on brain-protective mechanisms of autophagy associated circRNAs will illuminate an important feature of nervous system biology and will open the door to new approaches for treating neurodegenerative diseases.