The displacement of frataxin from the mitochondrial cristae correlates with abnormal respiratory supercomplexes formation and bioenergetic defects in cells of Friedreich ataxia patients

Davide Doni, Giovanni Rigoni, Elisa Palumbo, Elisa Baschiera, Roberta Peruzzo, Edith De Rosa, Federico Caicci, Leonardo Passerini, Daniela Bettio, Antonella Russo, Ildiko Szabò, Maria Eugenia Soriano, Leonardo Salviati, Paola Costantini; The FASEB Journal. 2021; 35:e21362. doi:10.1096/fj.202000524RR

In this work, we performed a comparative analysis of the mitochondrial phenotype of cell lines from FRDA patients, either homozygous for the expansion or compound heterozygotes for the G130V mutation. We found that, in healthy cells, FXN and two key proteins of the FeS‐cluster assembly machinery are enriched in mitochondrial cristae, the dynamic subcompartment housing the respiratory chain. On the contrary, FXN widely redistributes to the matrix in FRDA cells with defects in respiratory supercomplexes assembly and altered respiratory function. We propose that this could be relevant for the early mitochondrial defects afflicting FRDA cells and that perturbation of mitochondrial morphodynamics could in turn be critical in terms of disease mechanisms.

Retrotope Granted Rare Pediatric Disease Designation from FDA for Lead Development Candidate, RT001, in Two Life-Threatening Neurodegenerative Indications

LOS ALTOS, Calif., Feb. 25, 2021 (GLOBE NEWSWIRE) -- Retrotope, a clinical-stage biopharmaceutical company focused on the development of novel, first-in-class therapies for degenerative diseases, today announced that the U.S. Food and Drug Administration (FDA) has granted two rare pediatric disease designations to RT001, the company’s lead development candidate. The first rare pediatric disease designation is for the treatment of infantile neuroaxonal dystrophy (INAD), with the second covering the treatment of Friedreich’s ataxia (FA). In addition, RT001 has been granted Fast Track designation by the FDA for the treatment of FA and orphan drug designation by the European Medicines Agency (EMA) for the treatment of INAD. RT001 has previously been granted orphan drug designation in the U.S. for the treatment of multiple diseases, including FA, progressive supranuclear palsy (PSP) and PLA2G6-associated neurodegeneration, which includes INAD.

Modifiers of Somatic Repeat Instability in Mouse Models of Friedreich Ataxia and the Fragile X-Related Disorders: Implications for the Mechanism of Somatic Expansion in Huntington's Disease

Zhao X, Kumari D, Miller CJ, Kim GY, Hayward B, Vitalo AG, Pinto RM, Usdin K.; J Huntingtons Dis. 2021;10(1):149-163. doi: 10.3233/JHD-200423. PMID: 33579860.

In this review we will discuss mouse models of two non-CAG repeat expansion diseases, specifically the Fragile X-related disorders (FXDs) and Friedreich ataxia (FRDA). We will compare and contrast these models with mouse and patient-derived cell models of various other repeat expansion disorders and the relevance of these findings for somatic expansion in HD. We will also describe additional genetic factors and pathways that modify somatic expansion in the FXD mouse model for which no comparable data yet exists in HD mice or humans. These additional factors expand the potential druggable space for diseases like HD where somatic expansion is a significant contributor to disease impact.

Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich’s Ataxia: Clues of an “Out-Brain Origin” of the Disease From a Family Study

Petrillo S, Santoro M, La Rosa P, Perna A, Gallo MG, Bertini ES, Silvestri G and Piemonte F; Front. Neurosci. 15:638810. (2021) doi:10.3389/fnins.2021.638810

Under frataxin depletion, the endogenous stimulation of NRF2 in asymptomatic FRDA subjects may contribute to protect against the progressive oxidative damage, helping to prevent the onset of neurological symptoms and highlighting an “out-brain origin” of the disease.

Frataxins Emerge as New Players of the Intracellular Antioxidant Machinery

Uceda, A.B.; Donoso, J.; Frau, J.; Vilanova, B.; Adrover, M.; Antioxidants 2021, 10, 315. doi:10.3390/antiox10020315 

Consequently, our work proves that Yfh1 and Hfra are essential components of the intracellular antioxidant machinery, not only because they are able to regulate the detoxifying enzymatic mechanisms, but also because they directly act against the production of ROS. This latter mechanism also has further consequences since both proteins are able to unspecifically inhibit the oxidation of α-syn, which prove that they could act as molecular shields to protect a broad set of intracellular oxidation-prone proteins.

Energy deficit-independent stress response in the Frataxin-depleted heart: evidence that Integrated Stress Response can predominate over mTORC1 activation

Cesar Vasquez, Monika Patel, Aishwarya Sivaramakrishnan, Carmen Bekeova, Lauren Anderson-Pullinger, Nadan Wang, Hsin-Yao Tang, Erin L Seifert; bioRxiv 2020.06.12.148361; doi:10.1101/2020.06.12.148361 

 The lack of overt cardiac hypertrophy, consistent with lower global protein translation, suggests that ISR predominated over mTORC1 activation. Suppression of a major ATP demanding process could benefit the FXN-depleted heart, at least short term. Thus, the FXN-depleted heart may enter a protective state, not necessarily linked to a major energy deficit. Finally, we propose the model used here as a pre-clinical model of cardiomyopathy in FRDA.

Friedreich’s Ataxia and Auditory Processing Disorder

Teive, H.A., Iliadou, V.M. & Manto, M.; Cerebellum (2021). doi:10.1007/s12311-021-01238-7

The link between auditory deprivation (in this case of the form of APD) and cognition has long-term outcomes and should not be thought as a cross-sectional one [17, 18]. Thus, it is of outmost importance to longitudinally evaluate patients with ATX-FXN, document the cognitive deficits when identifying APD at an early stage, and provide appropriate management for these challenging patients. Could this improve patients’ quality of life? This remains to be confirmed. Furthermore, the issue of a possible use of these findings as a biomarker for longitudinal or therapeutic studies remains open and requires novel studies.

Auditory Phenotypic Variability in Friedreich’s Ataxia Patients

Koohi, N., Thomas-Black, G., Giunti, P., Doris-Eva Bamiou.; Cerebellum (2021). doi:10.1007/s12311-021-01236-9

To our knowledge, this is the first study to demonstrate an association between genotype and auditory spatial processing phenotype in patients with FRDA. Auditory temporal processing, neural sound conduction, spatial processing and speech perception were more severely affected in patients with GAA1 greater than 500 repeats. The results of our study may indicate that auditory deprivation plays a role in the development of mild cognitive impairment in FRDA patients.

Hereditary Ataxia: A Focus on Heme Metabolism and Fe-S Cluster Biogenesis

Chiabrando D, Bertino F, Tolosano E.; Int J Mol Sci. 2020 May 26;21(11):3760. doi: 10.3390/ijms21113760.

Mutations in genes involved in heme metabolism and Fe-S cluster biogenesis cause different forms of ataxia, like posterior column ataxia and retinitis pigmentosa (PCARP), Friedreich's ataxia (FRDA) and X-linked sideroblastic anemia with ataxia (XLSA/A). Despite great efforts in the elucidation of the molecular pathogenesis of these disorders several important questions still remain to be addressed. Starting with an overview of the biology of heme metabolism and Fe-S cluster biogenesis, the review discusses recent progress in the understanding of the molecular pathogenesis of PCARP, FRDA and XLSA/A, and highlights future line of research in the field.

Prognostic value of longitudinal strain and ejection fraction in Friedreich ataxia

L. Legrand, C. Heuze, A. Diallo, M.L. Monin, C. Ewenczyk, E. Vicaut, G. Montalescot, R. Isnard, A. Durr, F. Pousset. International Journal of Cardiology, Published:February 13, 2021 DOI:10.1016/j.ijcard.2021.02.032 

 In FA, LS was not an independent predictor of mortality, LVEF remained the only independent predictor in the present study.

Data Readout from Potentially Pivotal Phase 2/3 INAD Trial Expected 1H ‘01; Phase 2 ALS and Pivotal Phase 2/3 Friedreich’s Ataxia Trial Readouts Expected by Year-End

LOS ALTOS, Calif., Feb. 11, 2021 (GLOBE NEWSWIRE)​. RT001 Clinical Program Highlights: Friedreich’s Ataxia (FA) – Enrollment was completed in the ongoing pivotal Phase 2/3 trial of RT001 in FA in late 2020. Data from this trial is expected to read out by the end of 2021. Proof-of-concept for RT001 in FA was demonstrated in the company’s previously completed Phase 1/2 placebo-controlled trial. FA is a rare, debilitating, life-shortening pediatric neurodegenerative disease. Like INAD, FA qualifies for RPD designation and a RPD voucher from FDA.

Future Prospects of Gene Therapy for Friedreich’s Ataxia

Ocana-Santero, G.; Díaz-Nido, J.; Herranz-Martín, S.; Int. J. Mol. Sci. 2021, 22, 1815. doi:10.3390/ijms22041815 

Friedreich’s ataxia is an autosomal recessive neurogenetic disease that is mainly associated with atrophy of the spinal cord and progressive neurodegeneration in the cerebellum. The disease is caused by a GAA-expansion in the first intron of the frataxin gene leading to a decreased level of frataxin protein, which results in mitochondrial dysfunction. Currently, there is no effective treatment to delay neurodegeneration in Friedreich’s ataxia. A plausible therapeutic approach is gene therapy. Indeed, Friedreich’s ataxia mouse models have been treated with viral vectors en-coding for either FXN or neurotrophins, such as brain-derived neurotrophic factor showing promising results. Thus, gene therapy is increasingly consolidating as one of the most promising therapies. However, several hurdles have to be overcome, including immunotoxicity and pheno-toxicity. We review the state of the art of gene therapy in Friedreich’s ataxia, addressing the main challenges and the most feasible solutions for them.

Sheffield university team awarded £1.6m for drug research​​​​​​​ on motor neurone disease

Sheffield Telegraph; It will support their partnership with Aclipse Therapeutics to advance the translational development of M102 - a drug candidate for the treatment of motor neurone disease (MND). Aclipse says M102 may also have potential to treat Friedreich’s ataxia, Huntington's disease and Parkinson's disease.

Gauging Gait Disorders with a Method Inspired by Motor Control Theories: A Pilot Study in Friedreich’s Ataxia

Gouelle, A.; Norman, S.; Sharot, B.; Salabarria, S.; Subramony, S.; Corti, M. Gauging; Sensors 2021, 21, 1144. doi:10.3390/s21041144 

 Organization Scores demonstrated a longitudinal deterioration in the gait characteristics from independent ambulators to those who ambulated with a rollator. Variability Scores mostly reflected dynamic instability, which became greater as the requirement of an ambulation aid or the switch from a cane to a rollator was imminent. The global value given by the Global Ambulation Score, which takes into consideration both the Organization Score, the Variability Score, and the level of assistive device, demonstrated a logarithmic relationship with the SARA-GS. Overall, these results highlight that both components introduced should be analyzed concurrently and suggest that the Global Ambulation Score may be a valuable outcome measure for longitudinal disease progression.

Defective palmitoylation of transferrin receptor triggers iron overload in Friedreich's ataxia fibroblasts

Floriane Petit, Anthony Drecourt, Michaël Dussiot, Coralie Zangarelli, Olivier Hermine, Arnold Munnich, Agnes Rotig; Blood blood.2020006987. doi:10.1182/blood.2020006987 

 Here we report on abnormal cellular iron homeostasis in FRDA fibroblasts inducing a massive iron overload in the cytosol and mitochondria. We observe membrane transferrin receptor 1 (TfR1) accumulation, increased TfR1 endocytosis, and delayed transferrin recycling, ascribing this to impaired TfR1 palmitoylation. Frataxin deficiency is shown to reduce coenzyme A (CoA) availability for TfR1 palmitoylation. Finally, we demonstrate that artesunate, CoA, and dichloroacetate improve TfR1 palmitoylation and decrease iron overload, paving the road for evidence-based therapeutic strategies at the actionable level of TfR1 palmitoylation in FRDA.