Frataxin deficiency in proprioceptive neurons is causal to inflammatory and glial responses in dorsal root ganglia

Frataxin deficiency in proprioceptive neurons is causal to inflammatory and glial responses in dorsal root ganglia, Pauline Meriau, Laure Weill, Hélène Puccio, Cendra Agulhon, bioRxiv 2024.04.16.589410; doi:10.1101/2024.04.16.589410 

Our study revealed that proprioceptor FXN deficiency causes major changes in inflammatory macrophage and SGC gene transcription as well as macrophage and SGC number, highlighting molecular and cellular pathways that were sequentially altered, thus representing temporal signatures of FA ganglionopathy progression.

Deciphering the mechanisms of gene silencing induced by triplet-repeat expansions

Deciphering the mechanisms of gene silencing induced by triplet-repeat expansions. Nat. Plants (2024). doi:10.1038/s41477-024-01673-4 

A triplet repeat expansion in Arabidopsis induces gene silencing that results in a severe growth defect. We show that an interplay between a SUMO protease and histone readers of active and inactive marks is required for this gene silencing, which highlights the importance of post-translational modifiers in chromatin remodelling. 

Uncovering key players in gene silencing: Insights into plant growth and human diseases. APRIL 19, 2024​. Monash University biologists have shed light on the intricate molecular mechanisms that are responsible for gene silencing induced by expanded repeats in an international study published today in Nature Plants.

Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism

NEWS PROVIDED BY Life Science Alliance - New York April 17, 2024

Immunometabolism investigates the intricate relationship between the immune system and cellular metabolism. This study delves into the consequences of mitochondrial frataxin (FXN) depletion, the primary cause of Friedreich’s ataxia (FRDA), a debilitating neurodegenerative condition characterized by impaired coordination and muscle control. By using single-cell RNA sequencing, we have identified distinct cellular clusters within the cerebellum of an FRDA mouse model, emphasizing a significant loss in the homeostatic response of microglial cells lacking FXN. Remarkably, these microglia deficient in FXN display heightened reactive responses to inflammatory stimuli. Furthermore, our metabolomic analyses reveal a shift towards glycolysis and itaconate production in these cells. Remarkably, treatment with butyrate counteracts these immunometabolic changes, triggering an antioxidant response via the itaconate-Nrf2-GSH pathways and suppressing the expression of inflammatory genes. Furthermore, we identify Hcar2 (GPR109A) as a mediator involved in restoring the homeostasis of microglia without FXN. Motor function tests conducted on FRDA mice underscore the neuroprotective attributes of butyrate supplementation, enhancing neuromotor performance. In conclusion, our findings elucidate the role of disrupted homeostatic function in cerebellar microglia in the pathogenesis of FRDA. Moreover, they underscore the potential of butyrate to mitigate inflammatory gene expression, correct metabolic imbalances, and improve neuromotor capabilities in FRDA. 

 Sciarretta F, Zaccaria F, Ninni A, Ceci V, Turchi R, Apolloni S, Milani M, Della Valle I, Tiberi M, Chiurchiù V, D'Ambrosi N, Pedretti S, Mitro N, Volontè C, Amadio S, Aquilano K, Lettieri-Barbato D. Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism. Life Sci Alliance. 2024 Apr 17;7(7):e202402609. doi: 10.26508/lsa.202402609. PMID: 38631900; PMCID: PMC11024345.

A genome-wide spectrum of tandem repeat expansions in 338,963 humans

Ya Cui, Wenbin Ye, Jason Sheng Li, Jingyi Jessica Li, Eric Vilain, Tamer Sallam, Wei Li, A genome-wide spectrum of tandem repeat expansions in 338,963 humans, Cell, Volume 187, Issue 9, 2024, Pages 2336-2341.e5, doi:10.1016/j.cell.2024.03.004. 

Similarly, the prevalence of expanded GAA TR units in FXN, linked to Friedreich ataxia (FRDA), is less prevalent in East Asian samples than in other ancestries (Figure S1B). This observation again mirrors the low frequency of reported cases of FRDA in Japan.

A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis

Yimin Dong, Honglei Kang, Renpeng Peng, Zheming Liu, Fuben Liao, Shi-an Hu, Weizhong Ding, Pengju Wang, Pengchao Yang, Meipeng Zhu, Sibo Wang, Minglong Wu, Dawei Ye, Xin Gan, Feng Li, Kehan Song, A clinical-stage Nrf2 activator suppresses osteoclast differentiation via the iron-ornithine axis, Cell Metabolism, 2024, doi:10.1016/j.cmet.2024.03.005. 

Activating Nrf2 by small molecules is a promising strategy to treat postmenopausal osteoporosis. However, there is currently no Nrf2 activator approved for treating chronic diseases, and the downstream mechanism underlying the regulation of Nrf2 on osteoclast differentiation remains unclear. Here, we found that bitopertin, a clinical-stage glycine uptake inhibitor, suppresses osteoclast differentiation and ameliorates ovariectomy-induced bone loss by activating Nrf2. Mechanistically, bitopertin interacts with the Keap1 Kelch domain and decreases Keap1-Nrf2 binding, leading to reduced Nrf2 ubiquitination and degradation. Bitopertin is associated with less adverse events than clinically approved Nrf2 activators in both mice and human subjects. Furthermore, Nrf2 transcriptionally activates ferroportin-coding gene Slc40a1 to reduce intracellular iron levels in osteoclasts. Loss of Nrf2 or iron supplementation upregulates ornithine-metabolizing enzyme Odc1, which decreases ornithine levels and thereby promotes osteoclast differentiation. Collectively, our findings identify a novel clinical-stage Nrf2 activator and propose a novel Nrf2-iron-ornithine metabolic axis in osteoclasts.

Emerging therapies for childhood-onset movement disorders

Vogt, Lindseya,∗; Quiroz, Vicenteb,∗; Ebrahimi-Fakhari, Dariusb,c. Emerging therapies for childhood-onset movement disorders. Current Opinion in Pediatrics 36(3):p 331-341, June 2024. | DOI: 10.1097/MOP.0000000000001354 

 We highlight reports of new small molecule drugs for Tourette syndrome, Friedreich's ataxia and Rett syndrome. We also discuss developments in gene therapy for aromatic l-amino acid decarboxylase deficiency and hereditary spastic paraplegia, as well as current work exploring optimization of deep brain stimulation and lesioning with focused ultrasound.

Perioperative management and outcomes for posterior spinal fusion in patients with Friedreich ataxia: A single-center, retrospective study

O'Brien EM, Neiswinter N, Lin KY, Lynch D, Baldwin K, Profeta V, Flynn JM, Muhly WT. Perioperative management and outcomes for posterior spinal fusion in patients with Friedreich ataxia: A single-center, retrospective study. Paediatr Anaesth. 2024 Apr 24. doi: 10.1111/pan.14896. Epub ahead of print. PMID: 38655751. 

Seventeen patients were included in the final analysis. The mean age was 15 ± 2 years old and 47% were female. Preoperatively, 35% were wheelchair dependent, 100% had mild-to-moderate hypertrophic cardiomyopathy with preserved systolic function and no left ventricular outflow tract obstruction, 29% were on cardiac medications, and 29% were on pain medications. Intraoperatively, 53% had transesophageal echocardiography monitoring; 12% had changes in volume status on echo but no changes in function. Numerous combinations of total intravenous anesthetic agents were used, most commonly propofol, remifentanil, and ketamine. Baseline neuromonitoring signals were poor in four patients and one patient lost signals, resulting in 4 (24%) wake-up tests. The majority (75%) were extubated in the operating room. Postoperative complications were high (88%) and ranged from minor complications like nausea/vomiting (18%) to major complications like hypotension/tachycardia (29%) and need for extracorporeal membrane oxygenation support in one patient (6%).