PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia

Rodríguez-Pascau, Laura; Britti, Elena; Calap-Quintana, Pablo; Dong, Yi; Vergara, Cristina; Delaspre, Fabien; Medina-Carbonero, Marta; Tamarit, Jordi; Pallardó, Federico V.; González-Cabo, Pilar; Ros, Joaquim; Lynch, David R.; Martinell, Marc; Pizcueta, Pilar

doi:10.1016/j.nbd.2020.105162

Cited by 41 publications

(42 citation statements)

References 46 publications

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“…In FRDA, the age of symptoms onset relates to the degree of FXN loss, that itself inversely correlates with the size of GAA1 triplet expansion (Campuzano et al, 1997). Pathophysiologically, a decreased expression of FXN involves at the cellular level increased oxidative stress, defective energy production, calcium dyshomeostasis, and impaired mitochondrial biogenesis, leading to mitochondrial dysfunction (Rodríguez‐Pascau et al, 2021). Considering that the posterior associative cortices showing altered dynamics in FRDA patients with early age of symptoms onset are parts of the brain regions showing the highest energy consumption at rest (Buckner, Andrews‐Hanna, & Schacter, 2008), low FXN levels might particularly impact the neural dynamics of those brain areas during a critical period for brain development leading to sustained impairment in their neural dynamics stability.…”

Section: Discussionmentioning

confidence: 99%

Age of onset modulates resting‐state brain network dynamics in Friedreich Ataxia

Naeije

Coquelet

Wens

et al. 2021

Human Brain Mapping

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This magnetoencephalography (MEG) study addresses (i) how Friedreich ataxia (FRDA) affects the sub‐second dynamics of resting‐state brain networks, (ii) the main determinants of their dynamic alterations, and (iii) how these alterations are linked with FRDA‐related changes in resting‐state functional brain connectivity (rsFC) over long timescales. For that purpose, 5 min of resting‐state MEG activity were recorded in 16 FRDA patients (mean age: 27 years, range: 12–51 years; 10 females) and matched healthy subjects. Transient brain network dynamics was assessed using hidden Markov modeling (HMM). Post hoc median‐split, nonparametric permutations and Spearman rank correlations were used for statistics. In FRDA patients, a positive correlation was found between the age of symptoms onset (ASO) and the temporal dynamics of two HMM states involving the posterior default mode network (DMN) and the temporo‐parietal junctions (TPJ). FRDA patients with an ASO <11 years presented altered temporal dynamics of those two HMM states compared with FRDA patients with an ASO > 11 years or healthy subjects. The temporal dynamics of the DMN state also correlated with minute‐long DMN rsFC. This study demonstrates that ASO is the main determinant of alterations in the sub‐second dynamics of posterior associative neocortices in FRDA patients and substantiates a direct link between sub‐second network activity and functional brain integration over long timescales.

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Section: Discussionmentioning

confidence: 99%

Age of onset modulates resting‐state brain network dynamics in Friedreich Ataxia

Naeije

Coquelet

Wens

et al. 2021

Human Brain Mapping

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“…These promising results suggest that such a therapeutic strategy may be as effective as allogeneic HSCT. In addition, efforts to find pharmacological strategies targeting oxidative stress, inflammation, or compensatory mechanisms (antioxidant cocktail [ 93 ], leriglitazone [ 94 ], sobetirome [ 50 , 54 , 55 ]) are still present. It remains to be evaluated whether such treatments would be useful per se or in combination with HSCT strategies, at least to delay the onset of neurological concerns and permit a lengthening of the time window to allow transplantation.…”

Section: Human Diseasesmentioning

confidence: 99%

Peroxisomal ABC Transporters: An Update

Tawbeh

Gondcaille

Trompier

et al. 2021

IJMS

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ATP-binding cassette (ABC) transporters constitute one of the largest superfamilies of conserved proteins from bacteria to mammals. In humans, three members of this family are expressed in the peroxisomal membrane and belong to the subfamily D: ABCD1 (ALDP), ABCD2 (ALDRP), and ABCD3 (PMP70). These half-transporters must dimerize to form a functional transporter, but they are thought to exist primarily as tetramers. They possess overlapping but specific substrate specificity, allowing the transport of various lipids into the peroxisomal matrix. The defects of ABCD1 and ABCD3 are responsible for two genetic disorders called X-linked adrenoleukodystrophy and congenital bile acid synthesis defect 5, respectively. In addition to their role in peroxisome metabolism, it has recently been proposed that peroxisomal ABC transporters participate in cell signaling and cell control, particularly in cancer. This review presents an overview of the knowledge on the structure, function, and mechanisms involving these proteins and their link to pathologies. We summarize the different in vitro and in vivo models existing across the species to study peroxisomal ABC transporters and the consequences of their defects. Finally, an overview of the known and possible interactome involving these proteins, which reveal putative and unexpected new functions, is shown and discussed.

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“…Thus, it is possible to speculate that an increase of calcium can activate mitochondrial calpains, promoting NCLX cleavage, reducing its levels, and, in turn, decreasing mitochondrial calcium efflux, thus worsening the phenotype. These processes could be reversible since frataxin replacement using a construct that deliver frataxin directly to mitochondria (TAT‐MTS cs ‐FXN), 76 but also using leriglitazone, a PPARgamma agonist, 84 or calcitriol, both producing a significant increase of frataxin levels, resulted in increased NCLX levels and reduction of neurite degeneration and cell death 84,85 . Consistently, many efforts are currently made to find compounds able to increase frataxin amounts as an obvious strategy for therapy.…”

Section: The Role Of Calcium In Friedreich Ataxiamentioning

confidence: 99%

Mitochondrial iron and calcium homeostasis in Friedreich ataxia

et al. 2021

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Friedreich Ataxia is a neuro‐cardiodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. Many evidences indicate that frataxin deficiency causes an unbalance of iron homeostasis. Nevertheless, in the last decade many results also highlighted the importance of calcium unbalance in the deleterious downstream effects caused by frataxin deficiency. In this review, the role of these two metals has been gathered to give a whole view of how iron and calcium dyshomeostasys impacts on cellular functions and, as a result, which strategies can be followed to find an effective therapy for the disease.

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PPAR gamma agonist leriglitazone improves frataxin-loss impairments in cellular and animal models of Friedreich Ataxia

Cited by 41 publications

References 46 publications

Age of onset modulates resting‐state brain network dynamics in Friedreich Ataxia

Age of onset modulates resting‐state brain network dynamics in Friedreich Ataxia

Peroxisomal ABC Transporters: An Update

Mitochondrial iron and calcium homeostasis in Friedreich ataxia

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