Multifaceted nanoparticles: emerging mechanisms and therapies in neurodegenerative diseases

Mistretta, M., Farini, A., Torrente, Y., & Villa, C. (2023). Brain : a journal of neurology, awad014. Advance online publication. doi:10.1093/brain/awad014 

 This review focuses on the use of nanosystems as an encouraging therapeutic approach targeting molecular pathways involved in localized and systematic neurodegenerative diseases. Among this latter, Friedreich's ataxia is an untreatable complex multisystemic disorder and the most spread type of ataxia, that represents a test case to validate the clinical potential of therapeutic strategies based on nanoparticles with pleiotropic effects.

Decreased mitochondrial respiration in cardiac fibers isolated from a mouse model of Friedreich’s ataxia

PT Pierce, X Wang, A Rivera, A Cooper, H Van Remmen, J Brown, PF Vitiello, The American Journal of the Medical Sciences, Volume 365, Supplement 1, 2023, Pages S194-S195, ISSN 0002-9629, doi:10.1016/S0002-9629(23)00372-5. 

Since mitochondrial complex activities of cardiac fibers from FRDAkD mice were impaired without changes in mitochondrial mass, we hypothesize that bioenergetic changes could be attributable to altered fragmentation of the mitochondrial network. This is the first set of data providing ex vivo evidence of mitochondrial respiratory defects during FXN knockdown associated with FRDA. Furthermore, these findings highlight that there are tissue-specific mechanisms during FXN loss since cardiac and skeletal muscle fibers had differential bioenergetic responses.

Foot and Ankle Biomechanics

Morgan E. Leslie, Joseph M. Iaquinto, Chapter 31 - Neurological Foot Pathology, Editor(s): William R. Ledoux, Scott Telfer, Academic Press, 2023, Pages 489-506, ISBN 9780128154496, doi:10.1016/B978-0-12-815449-6.00047-0. 

This chapter provides an overview of pathologies involving neurological mechanisms affecting foot and ankle biomechanics including stroke, cerebral palsy, toe walking, peripheral neuropathy, foot drop, tarsal tunnel syndrome, Morton’s neuroma, Charcot foot, Charcot-Marie-Tooth disease, Friedreich’s ataxia, and poliomyelitis.

Interactions of reactive sulfur species with metalloproteins

ndrea Domán, Éva Dóka, Dorottya Garai, Virág Bogdándi, György Balla, József Balla, Péter Nagy; Redox Biology, 2023, 102617, ISSN 2213-2317, doi:10.1016/j.redox.2023.102617. 

The current review summarizes the interactions of RSS with protein metal centers and their biological implications with special emphasis on mechanistic aspects, sulfide-mediated signaling, and pathophysiological consequences. A deeper understanding of the biological actions of reactive sulfur species on a molecular level is primordial in H2S-related drug development and the advancement of redox medicine.

Peroxisome proliferator-activated receptor (PPAR) agonists as a potential therapy for inherited metabolic disorders

Bianca Seminotti, Mateus Grings, Nícolas Manzke Glänzel, Jerry Vockley, Guilhian Leipnitz; Biochemical Pharmacology, 2023, 115433, ISSN 0006-2952, doi:10.1016/j.bcp.2023.115433. 

Peroxisomal proliferator-activated receptors (PPARs) consist of a group of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ) that regulate multiple cellular functions and processes, including response to oxidative stress, inflammation, lipid metabolism, and mitochondrial bioenergetics and biogenesis. In this context, the activation of PPARs has been shown to stimulate oxidative phosphorylation and reduce reactive species levels. Thus, pharmacological treatment with PPAR activators, such as fibrates, has gained much attention in the last 15 years. This review summarizes preclinical (animal models and patient-derived cells) and clinical data on the effect of PPARs in IMDs.

A new FRDA mouse model [Fxnnull:YG8s(GAA) > 800] with more than 800 GAA repeats

Kalef-Ezra E, Edzeamey FJ, Valle A, Khonsari H, Kleine P, Oggianu C, Al-Mahdawi S, Pook MA and Anjomani Virmouni S (2023) . Front. Neurosci. 17:930422. doi: 10.3389/fnins.2023.930422 

We found statistically significant behavioral deficits, together with reduced levels of frataxin mRNA and protein, and aconitase activity in YG8JR mice compared with control Y47JR mice. YG8JR mice exhibit intergenerational GAA repeat instability by the analysis of parent and offspring tissue samples. Somatic GAA repeat instability was also detected in individual brain and cerebellum tissue samples. In addition, increased DNA methylation of CpG U13 was identified in FXN GAA repeat region in the brain, cerebellum, and heart tissues. Furthermore, we show decreased histone H3K9 acetylation and increased H3K9 methylation of YG8JR cerebellum tissues within the FXN gene, upstream and downstream of the GAA repeat region compared to Y47JR controls.

A Gene-Edited Cell Therapy for an Incurable Disease: Researchers Receive USD 4.8M Grant to Treat Friedreich’s Ataxia

By: Rebecca Roberts - Jan. 23, 2023. Professor Stephanie Cherqui of University of California San Diego’s School of Medicine recently received a prestigious grant from the Californian Institute of Regenerative Medicine, which will allow her and her team to bring her novel CRISPR therapy for the fatal neurodegenerative disease Friedreich’s ataxia to the clinic. Cherqui’s novel treatment for FRDA is an ex vivo gene-edited autologous cell therapy. The process begins with extracting haematopoietic stem and progenitor cells (HSPCs) from the peripheral blood of patients before excising the trinucleotide repeat hyperexpansion in intron 1 of the FXN gene from the cells. This edit involves delivering a ribonucleoprotein (RNP) complex consisting of Cas9 and two sgRNAs – one guide for either end of the trinucleotide expansion. In their original proof-of-concept study, the team were able to achieve editing efficiencies of more than 50% in the HSPCs of FRDA patients. Edited HSPCs display restored expression of frataxin and mitochondrial function, and can be transplanted back to patients as a one-time, curative therapy. »Because this mutation is located within an intron in the FXN gene, it is a good target for gene correction by removing this expansion using CRISPR-Cas9. In addition, this approach would be valid for all FRDA patients, because they all carry a trinucleotide expansion mutation,« Cherqui elaborates. Edited HSPCs are currently used for the treatment of blood disorders such as sickle cell disease and β-thalassemia. However, Cherqui’s work is novel because it offers proof that these cells can be used to treat conditions like FRDA. Edited HSPCs are able to proliferate and differentiate into macrophages and microglia in vivo in mice, and traffic to the necessary tissues throughout the body and brain of FRDA patients. The early data shows that transplantation of the corrected HSPCs in mice prevents disease progression. The therapy will be aimed at the treatment of babies and children in whom the disease has not yet caused significant damage, however, Cherqui says they may also be able to halt disease progression in adult patients.

A Gene-Edited Cell Therapy for an Incurable Disease: Researchers Receive USD 4.8M Grant to Treat Friedreich’s Ataxia

Protoporphyrin IX Binds to Iron(II)-Loaded and to Zinc-Loaded Human Frataxin

Bernardo-Seisdedos G, Schedlbauer A, Pereira-Ortuzar T, Mato JM, Millet O.; Life (Basel). 2023 Jan 12;13(1):222. doi: 10.3390/life13010222. PMID: 36676171. 

We demonstrate that frataxin also binds Zn2+ in a structurally similar way to Fe2+, but with lower affinity. In turn, both Fe2+-loaded and Zn2+-loaded frataxins specifically associate to protoporphyrin IX with micromolar affinity, while apo-frataxin does not bind to the porphyrin. Protoporphyrin IX association to metal-loaded frataxin shares the binding epitope with ferrochelatase.

Small-molecule inhibitors of proteasome increase CjCas9 protein stability

Yaméogo P, Majeau N, Mbakam CH, Tremblay JP (2023) . PLoS ONE 18(1): e0280353. doi:10.1371/journal.pone.0280353 

We observed that the CjCas9 protein expressed in HEK293T cells after transfection of this transgene under a CMV promoter was much lower than the SpCas9 protein in the same conditions. We thus evaluated the effect of proteasome inhibitors on CjCas9 protein stability and its efficiency on FXN gene editing. Western blotting showed that the addition of MG132 or bortezomib, significantly increased CjCas9 protein levels in HEK293T and HeLa cells. Moreover, bortezomib increased the level of CjCas9 protein expressed under promoters weaker than CMV such as CBH or EFS but which are specific for certain tissues. Finally, ddPCR quantification showed that bortezomib treatment enhanced CjCas9 efficiency to delete GAA repeat region of FXN gene in HEK293T cells. The improvement of CjCas9 protein stability would facilitate its used in CRISPR/Cas system.

A wearable motion capture suit and machine learning predict disease progression in Friedreich’s ataxia

Balasundaram Kadirvelu, Constantinos Gavriel, Sathiji Nageshwaran, Jackson Ping Kei Chan, Suran Nethisinghe, Stavros Athanasopoulos, Valeria Ricotti, Thomas Voit, Paola Giunti, Richard Festenstein & A. Aldo Faisal; Nat Med (2023). doi:10.1038/s41591-022-02159-6

Our work demonstrates how data-derived wearable biomarkers can track personal disease trajectories and indicates the potential of such biomarkers for substantially reducing the duration or size of clinical trials testing disease-modifying therapies and for enabling behavioral transcriptomics.