Human Mitochondrial Ferredoxin 1 (FDX1) and Ferredoxin 2 (FDX2) Both Bind Cysteine Desulfurase and Donate Electrons for Iron–Sulfur Cluster Biosynthesis

Cai K, Tonelli M, Frederick RO, Markley JL. Biochemistry. 2017;56(3):487-499. doi:10.1021/acs.biochem.6b00447.

Physical Therapy for Cerebellar Ataxia

Akiyoshi Matsugi (2017). Physical Therapy for Cerebellar Ataxia, Neurological Physical Therapy, Prof. Toshiaki Suzuki (Ed.), InTech, ISBN 978-953-51-3114-4, Print ISBN 978-953-51-3113-7, Published: May 10, 2017 under CC BY 3.0 license.

Intensive physical therapy more than 1 hour per day for at least 4 weeks, focused on balance, gait, and strength training in hospital and home for patients with degenerative cerebellar ataxia can improve ataxia, gait ability, and activity of daily living. Furthermore, the weighting on the torso, using treadmill, noninvasive brain stimulation over the cerebellum for neuromodulation to facilitate motor learning, and neurophysiological assessment have a potential to improve the effect of physical therapy on cerebellar ataxia. Previous findings indicated that physical therapy is time restricted; therefore, its long-term effect and the effect of new optional neurophysiological methods should be studied.

Inducible And Reversible Phenotypes In A Novel Mouse Model Of Friedreich's Ataxia

Vijayendran Chandran, Kun Gao, Vivek Swarup, Revital Versano, Hongmei Dong, Maria C. Jordan, Daniel H. Geschwind; bioRxiv 137265 This article is a preprint and has not been peer-reviewed doi:10.1101/137265

We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset, progression and potential rescue of disease phenotypes by the modulation of Fxn levels using RNA interference. We found that systemic knockdown of Fxn in adult mice led to multiple features paralleling those observed in human patients, including electrophysiological, cellular, biochemical and structural phenotypes associated with cardiomyopathy, as well as dorsal root ganglion and retinal neuronal degeneration and reduced axonal size and myelin sheath thickness in the spinal cord. Fxn knockdown mice also exhibited other abnormalities similar to patients, including weight loss, reduced locomotor activity, ataxia, reduced muscular strength, and reduced survival, as well as genome-wide transcriptome changes. The reversibility of knockdown also allowed us to determine to what extent observed phenotypes represent neurodegenerative cell death, or reversible cellular dysfunction.

Remarkably, upon restoration of near wild-type FXN levels, we observed significant recovery of function, pathology and associated transcriptomic changes, even after significant motor dysfunction was observed.

Erythropoietin and small molecule agonists of the tissue-protective erythropoietin receptor increase FXN expression in neuronal cells in vitro and in Fxn-deficient KIKO mice in vivo

James L. Miller, Myriam Rai, Normand L. Frigon, Massimo Pandolfo, Juha Punnonen, Jeffrey R. Spencer; Neuropharmacology, Available online 11 May 2017, ISSN 0028-3908, doi:10.1016/j.neuropharm.2017.05.011.

STS-E412 and STS-E424 are novel small molecule agonists of the tissue-protective, but not the erythropoietic EPO receptor. We find that rhEPO, STS-E412 and STS-E424 increase FXN expression in vitro and in vivo. RhEPO, STS-E412 and STS-E424 increase FXN by up to 2-fold in primary human neuronal cells and in retinoic-acid differentiated murine P19 cells. In primary human cortical cells, the increase in FXN protein was accompanied by an increase in FXN mRNA, detectable within 4 h. RhEPO and low nanomolar concentrations of STS-E412 and STS-E424 also increase FXN in normal and FRDA patient-derived PBMC by 20%–40% within 24 h, an effect that was comparable to that by HDAC inhibitor 4b. Unexpectedly, rhEPO-treated KIKO mice developed severe splenomegaly, while no splenomegaly was observed in STS-E412- or STS-E424-treated mice. RhEPO, STS-E412 and STS-E424 upregulate FXN expression in vitro at equal efficacy, however, the effects of the small molecules on FXN expression in the CNS are superior to rhEPO in vivo.

STS-E412 (2-[2-(4-chlorophenoxy)ethoxy]-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine),nonpeptidyl compound selective activator of the tissue-protective EPOR/CD131 receptor.

Building the patient community

F Raffai and O Timmis; Gene Therapy (3 May 2017) doi:10.1038/gt.2017.

There are many challenges in conducting rare disease research. The conditions are often poorly understood, small patient populations are dispersed around the world, and there are limited funding opportunities. Patient groups can serve as a key partner in overcoming these challenges, as they understand the impact of rare conditions on patients’ lives. This gives patient groups valuable scientific insights into the disease. This can be used to create research strategies, address research bottlenecks and directly fund research that appropriately addresses patient needs. Patient groups can also play a critical role in recruiting and retaining patients for clinical trials, which reduces time and resource waste. By partnering with patient groups, research teams can improve efficiency of research and best meet the needs of patients. Researchers can also play an important role in building and supporting patient groups to unlock these benefits.

Improve Compassionate Use Programmes to ensure patients’ early access to medicines

EURORDIS-Rare Diseases Europe has published a new position on compassionate use, calling for the adoption of measures to revolutionise patients’ access to new medicines through Compassionate Use Programmes (CUP).

The length of time needed to develop a medicine varies, but on average it takes five to seven years, usually followed by the regulatory process and its legal timeframe, followed finally by pricing and reimbursement negotiations. Not all patients have the time to contemplate this relatively long process: their disease worsens, they gradually lose their body functions, and eventually die. In addition, at the same time as this inescapable deterioration is taking place, they can hear about “promising results” coming in the news, in real time. No other situation can be a source of greater despair in a patient’s life: dying and yet being aware a possible medicine is approaching the market.

Mechanisms of iron- and copper-frataxin interactions

Thi Hong Lien Han, Jean-Michel Camadro, Renata Santos, Emmanuel Lesuisse, Jean Michel El Hage Chahine and Nguyêt Thanh Ha-Duong; Metallomics, 2017, Accepted Manuscript. DOI:10.1039/C7MT00031F

Frataxin deficient Δyfh1 yeast cells exhibited a marked growth defect in the presence of exogenous Cu or Mn. Mitochondria from Δyfh1 strains accumulated also higher amounts of copper, suggesting a functional role of frataxin in vivo in copper homeostasis.

Peripheral nerve ultrasound in friedreich’s ataxia

Eoin Mulroy, Luciana Pelosi, Purwa Joshi, Ruth Leadbetter, Miriam Rodrigues, Stuart Mossman, Richard Roxburgh; J Neurol Neurosurg Psychiatry 2017;88:e1. doi:10.1136/jnnp-2017-316074.59

The ultrasound finding of enlarged peripheral nerves in FRDA patients points to a structural abnormality at peripheral nerve level. This contrasts with the reduced cross-sectional area seen in the cerebellar ataxia, neuronopathy, vestibular areflexia syndrome (CANVAS) which is thought to be due to a pure sensory ganglionopathy (Pelosi et al, Muscle Nerve 2017, in press). While the specific pathophysiology in FRDA is unknown, nerve enlargement suggests, in agreement with recent neuropathological studies, that axonal loss from dorsal root ganglionopathy is not the sole mechanism underlying sensory neuropathy of FRDA. Myelin and/or stromal abnormality at peripheral nerve level may play a significant role.

Plasma metabolomics reveals a diagnostic metabolic fingerprint for mitochondrial aconitase (ACO2) deficiency

Abela L, Spiegel R, Crowther LM, Klein A, Steindl K, Papuc SM, Joset P, Zehavi Y, Rauch A, Plecko B, Simmons TL. PLoS ONE 12(5): e0176363. Doi:10.1371/journal.pone.0176363

Neurotoxicity induced by mitochondrial oxidative stress has been demonstrated for several neurodegenerative disorders. Furthermore, reduced aconitase activity has been found in Huntington disease, progressive supranuclear palsy, Friedreich ataxia and Alzheimer’s disease.
We demonstrate that metabolome profiling is a powerful tool to characterize disease mechanisms and pathogenicity of mutations.

Normalization of timed neuropsychological tests with the PATA rate and nine-hole pegboard tests

Saccà, F., Costabile, T., Abate, F., Liguori, A., Paciello, F., Pane, C., De Rosa, A., Manganelli, F., De Michele, G. and Filla, A. Journal of Neuropsychology. doi: 10.1111/jnp.12125

We tested the method on 24 patients with Friedreich Ataxia (FRDA), as a model of motor and speech impairment. In healthy controls, phonation or hand movement is 13.5–61.7% of total test time. In FRDA patients, the effect of normalization improved all test results (range: 0.51–48.4%; p < .001). FRDA patients had worst scores in all tests when compared to controls, and the difference remained significant after correction except for the Attentional Matrices. At the individual level, the normalization method improved equivalent scores with fever patients showing impaired scores after correction.