The psychosocial situation of families caring for children with rare diseases during the COVID-19 pandemic: results of a cross-sectional online survey

Lydia Rihm, Mareike Dreier, Farhad Rezvani, Silke Wiegand-Grefe & Jörg Dirmaier; Orphanet J Rare Dis 17, 449 (2022). doi:10.1186/s13023-022-02595-0 

 This study indicates a high psychosocial burden on family caregivers of children with RDs during the early COVID-19 pandemic, characterized by high distress levels and wide-ranging everyday problems, unmet psychosocial information needs, and reduced caregiver-reported HRQoL in children with RDs. The findings highlight the ongoing need for target group-specific, low-threshold support services (e.g., websites) during and after the pandemic.

Social concepts and the cerebellum: behavioural and functional connectivity signatures in cerebellar ataxic patients

Lopes da Cunha Pamela, Fittipaldi Sol, González Campo Cecilia, Kauffman Marcelo, Rodríguez-Quiroga Sergio, Yacovino Darío Andrés, Ibáñez Agustín, Birba Agustina and García Adolfo M. 2023; Phil. Trans. R. Soc., B3782021036420210364, doi:10.1098/rstb.2021.0364 

We compared behavioural outcomes between groups and examined their association with cerebellar connectivity. CA patients showed deficits in social text comprehension and normal scores in the non-social text. Also, social text outcomes in controls selectively correlated with connectivity between the cerebellum and key regions subserving multi-modal semantics and social cognition, including the superior and medial temporal gyri, the temporal pole and the insula. Conversely, brain-behaviour associations involving the cerebellum were abolished in the patients. Thus, cerebellar structures and connections seem involved in processing social concepts evoked by naturalistic discourse. Such findings invite new theoretical and translational developments integrating social neuroscience with embodied semantics.

Protection of dystrophic muscle cells using Idebenone correlates with the interplay between calcium, oxidative stress and inflammation

Amanda Harduim Valduga, Daniela Sayuri Mizobuti, Fernanda dos Santos Rapucci Moraes, Rafael Dias Mâncio, Luis Henrique Rapucci Moraes, Túlio de Almeida Hermes, Aline Barbosa Macedo, Elaine Minatel; Int J Exp Path. 2022; 00: 1- 9. doi:10.1111/iep.12463 

The Idebenone treatment was able to reduce the levels of oxidative stress markers, such as H2O2 and 4-HNE, as well as decreasing intracellular calcium influx in the dystrophic muscle cells. Regarding Idebenone effects on the anti-oxidant defence system, an up-regulation of catalase levels, glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity was observed in the dystrophic muscle cells. In addition, the Idebenone treatment was also associated with reduction in inflammatory molecules, such as nuclear factor kappa-B (NF-κB) and tumour necrosis factor (TNF) in mdx muscle cells.

Astrocytic mitochondrial frataxin—A promising target for ischemic brain injury

Hazra, R, Novelli, EM, Hu, X.; CNS Neurosci Ther. 2022; 00: 1- 6. doi:10.1111/cns.14068 

In the ischemic brain, hypoxia leads to mitochondrial dysfunction, insufficient energy production, and astrocyte activation. Yet, most studies investigating mitochondrial dysfunction in cerebral ischemia have focused exclusively on neurons. This review will highlight the importance of the morphological, molecular, and functional heterogeneity of astrocytes in their role in brain injuries and explore how activated astrocytes exhibit calcium imbalance, reactive oxygen species overproduction, and apoptosis. In addition, special focus will be given to the role of the mitochondrial protein frataxin in activated astrocytes during ischemia and its putative role in the pharmacological management of cerebral ischemia.

Study traces shared and unique cellular hallmarks found in 6 neurodegenerative diseases

ScienceDaily, 21 December 2022. Arizona State University. 

In a study appearing in the current issue of Alzheimer's & Dementia: The Journal of the Alzheimer' Association, corresponding author Carol Huseby of Arizona State University and her colleagues look at cellular alterations in six distinct neurodegenerative diseases: amyotrophic lateral sclerosis or Lou Gehrig's disease, Alzheimer's disease, Friedreich's ataxia, frontotemporal dementia, Huntington's disease and Parkinson's disease. The selected RNA transcripts reveal eight common themes across the six neurodegenerative diseases: transcription regulation, degranulation (a process involved in inflammation), immune response, protein synthesis, cell death or apoptosis, cytoskeletal components, ubiquitylation/proteasome (involved in protein degradation) and mitochondrial complexes (which oversee energy usage in cells). The eight cellular dysfunctions uncovered are associated with identifiable pathologies in the brain characteristic of each disease.

Blood RNA transcripts reveal similar and differential alterations in fundamental cellular processes in Alzheimer's disease and other neurodegenerative diseases

Carol J. Huseby, Elaine Delvaux, Danielle L. Brokaw, Paul D. Coleman; Alzheimer's & Dementia, 2022; DOI: 10.1002/alz.12880 

 We report that transcripts of the blood transcriptome selected for each of the neurodegenerative diseases represent fundamental biological cell processes including transcription regulation, degranulation, immune response, protein synthesis, apoptosis, cytoskeletal components, ubiquitylation/proteasome, and mitochondrial complexes that are also affected in the brain and reveal common themes across six neurodegenerative diseases.

Efficacy and Safety of Leriglitazone in Patients With Friedreich Ataxia: A Phase 2 Double-Blind, Randomized Controlled Trial (FRAMES)

Pandolfo M, Reetz K, Darling A, Rodriguez de Rivera FJ, Henry PG, Joers J, Lenglet C, Adanyeguh I, Deelchand D, Mochel F, Pousset F, Pascual S, Van den Eede D, Martin-Ugarte I, Vilà-Brau A, Mantilla A, Pascual M, Martinell M, Meya U, Durr A.; Neurol Genet. 2022 Nov 1;8(6):e200034. doi: 10.1212/NXG.0000000000200034. 

The primary endpoint of change in spinal cord area was not met. Secondary endpoints provide evidence supporting proof of concept for leriglitazone mode of action and, with acceptable safety data, support larger studies in patients with FRDA.

Design and Delivery of SINEUP: A New Modular Tool to Increase Protein Translation

Arnoldi M, Zarantonello G, Espinoza S, Gustincich S, Di Leva F, Biagioli M.; Methods Mol Biol. 2022;2434:63-87. doi: 10.1007/978-1-0716-2010-6_4. 

Synthetic SINEUP is thus a novel molecular tool that potentially may be used for any industrial or biomedical application to enhance protein production, also as possible therapeutic strategy in haploinsufficiency-driven disorders.Here, we describe a detailed protocol to (1) design a specific BD directed to a gene of interest and (2) assemble and clone it with the ED to obtain a functional SINEUP molecule. Then, we provide guidelines to efficiently deliver SINEUP into mammalian cells and evaluate its ability to effectively upregulate target protein translation.

Recurrent repeat expansions in human cancer genomes

Erwin, G.S., Gürsoy, G., Al-Abri, R. et al.; Nature (2022). doi:10.1038/s41586-022-05515-1 

Expansions of tandem DNA repeats (TRs) are known to cause more than 50 devastating human diseases, including Huntington’s disease and fragile X syndrome1,2. TR tracts that cause human disease are typically large (more than 100 bp)1. However, identifying large TRs with short-read DNA sequencing methods is difficult because the repeat sequences are ubiquitous in the genome and many are too large—larger than the typical sequencing read length—to uniquely map to the reference genome9. Thus, many large TRs go undetected with current genomic technologies, and, despite their importance to monogenic disease, the frequency and function of recurrent repeat expansions (rREs) are unknown in complex human genetic diseases such as cancer.

Researchers may have found a new path for halting cancer cell production

Stanford Medicine; December 14, 2022; 

The project began not with cancer, but with a rare, neurodegenerative disease without a cure, Friedreich ataxia. Five years ago, Erwin, then a graduate student at the University of Wisconsin-Madison, was exploring the genetic underpinnings of Friedreich ataxia in hopes of filling the therapeutic void. Erwin knew that DNA mutations called repeat expansions cause Friedreich ataxia, along with dozens of other serious conditions, many neurological. 

Repeat expansions are stretches of DNA that erroneously repeat themselves dozens to thousands of times in the genome. 

 Testing the molecule in cells from a Friedreich ataxia patient, Erwin saw that Syn-TEF1 successfully targeted the repeat expansion, helping RNA polymerase move through it to transcribe the FXN gene, bringing frataxin to normal levels. Due to its success in cells, researchers are now testing the safety and dosage of a version of Syn-TEF1 in Friedreich ataxia patients.