Pseudodominance in Friedreich ataxia – impact of high prevalence of carriers and intrafamilial clinical variation

Malaquias, M.J., Oliveira, J., Santos, M., Brandão, A.F., Sardoeira, A., Sequeiros, J., Barros, J. and Damásio, J. (2023), Pseudodominance in Friedreich ataxia – impact of high prevalence of carriers and intrafamilial clinical variation. Mov Disord Clin Pract. Accepted Author Manuscript. https://doi.org/10.1002/mdc3.13694 

 Clinicians should be aware of the possibility of pseudodominance when facing an apparent autosomal dominant pedigree, particularly in disorders with high frequency of carriers and variable expression. Otherwise, genetic diagnoses may be delayed.

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.

Omaveloxolone: An activator of Nrf2 for the treatment of Friedreich's ataxia

Profeta, V., McIntyre, K., Wells, M., Park, C., & Lynch, D. R. (2023). Expert opinion on investigational drugs, 10.1080/13543784.2023.2173063. Advance online publication. doi:10.1080/13543784.2023.2173063 

 Although the neurologic phenotype of FRDA is well-defined, there are currently no established pharmacological treatments. Omaveloxolone, a nuclear factor erythroid 2-related factor 2 (Nrf2) activator, is currently under review by the Food and Drug Administration (FDA) and has the potential to be the first approved treatment for FRDA. In the present report, we have reviewed the basic and clinical literature on Nrf2 deficiency in FRDA, and evidence for the benefit of omaveloxolone.

Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets

Konrad Teodor Sawicki, Adam De Jesus and Hossein Ardehali; Circulation Research. 2023;132:379–396, doi:10.1161/CIRCRESAHA.122.321667 

 Iron dysregulation ranges from iron deficiency to iron overload and is seen in many types of cardiovascular disease, including heart failure, myocardial infarction, anthracycline-induced cardiotoxicity, and Friedreich’s ataxia. Recently, the use of intravenous iron therapy has been advocated in patients with heart failure and certain criteria for iron deficiency. Here, we provide an overview of systemic and cellular iron homeostasis in the context of cardiovascular physiology, iron deficiency, and iron overload in cardiovascular disease, current therapeutic strategies, and future perspectives.

Deficient mitochondrial respiration impairs sirtuin activity in dorsal root ganglia in Friedreich Ataxia mouse and cell models

Arabela Sanz-Alcazar, Elena Britti, Fabien Delaspre, Marta Medina-Carbonero, Maria Pazos-Gil, Jordi Tamarit, Joaquim ROS, Elisa Cabiscol bioRxiv 2023.02.01.526688; doi:10.1101/2023.02.01.526688

In the present study, we found that in primary cultures of DRG neurons as well as in DRGs from the FXNI151F mouse model, frataxin deficiency resulted in lower activity and levels of the electron transport complexes, mainly complexes I and II. As a consequence, the NAD+/NADH ratio was reduced and SirT3, a mitochondrial NAD+-dependent deacetylase, was impaired. We identified alpha tubulin as the major acetylated protein from DRG homogenates whose levels were increased in FXNI151F mice compared to WT mice.