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Scientific News

FARA funds research progress

In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA’s Grant Program and the Treatment Pipeline.

 


 

HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model

Friedreich ataxia, an autosomal recessive neurodegenerative and cardiac disease, is caused by abnormally low levels of frataxin, an essential mitochondrial protein. All Friedreich ataxia patients carry a GAA⋅TTC repeat expansion in the first intron of the frataxin gene, either in the homozygous state or in compound heterozygosity with other loss-of-function mutations. The GAA expansion inhibits frataxin expression through a heterochromatin-mediated repression mechanism. Histone modifications that are characteristic of silenced genes in heterochromatic regions occur at expanded alleles in cells from Friedreich ataxia patients, including increased trimethylation of histone H3 at lysine 9 and hypoacetylation of histones H3 and H4.

Read More: HDAC Inhibitors Correct Frataxin Deficiency in a Friedreich Ataxia Mouse Model

Structural basis of the iron storage function of frataxin from single-particle reconstruction of the iron-loaded oligomer

The mitochondrial protein frataxin plays a central role in mitochondrial iron homeostasis, and frataxin deficiency is responsible for Friedreich ataxia, a neurodegenerative and cardiac disease that affects 1 in 40000 children. Here we present a single-particle reconstruction from cryoelectron microscopic images of iron-loaded 24-subunit oligomeric frataxin particles at 13 and 17 Å resolution. Computer-aided classification of particle images showed heterogeneity in particle size, which was hypothesized to result from gradual accumulation of iron within the core structure. Thus, two reconstructions were created from two classes of particles with iron cores of different sizes. The reconstructions show the iron core of frataxin for the first time.

Read More: Structural basis of the iron storage function of frataxin from single-particle reconstruction ...

Orthopedic shoes improve gait in Friedreich's ataxia: a clinical and quantified case study

Our aim was to evaluate with modern tools the efficacy of orthopedic shoes on gait disorders in Friedreich's ataxia. The case of a 26-year-old woman with Friedreich's ataxia is described. She mainly complained of fatigability, ankle instability, frequent falls and pain. Impairments involved a cerebellar syndrome, a proprioceptive deficit, an upper motor neurone syndrome and osteoarticular deformities. Gait disabilities included ataxia and requirement of a cane. Handicap concerned outings, altering quality of life. Orthopedic shoes combined with physical therapy were prescribed. Assessment of treatment was planned after one month. Self-assessment by the patient was noted. Clinical assessment was provided by physical examination and clinical gait analysis supported by video. Quantified assessment was performed with a Gaitrite system recording spatiotemporal gait parameters.

Read More: Orthopedic shoes improve gait in Friedreich's ataxia: a clinical and quantified case study

Friedreich's ataxia and scoliosis: the experience at two institutions

PURPOSE:
Friedreich's ataxia is a genetically transmitted, progressive spinocerebellar degenerative disease characterized by ataxia. The purpose of this study is to evaluate the demographics, progression, nonoperative, and operative treatment of spinal deformities in patients with Friedreich's ataxia at 2 tertiary pediatric orthopaedic hospitals.

METHODS:
After institutional review board approval, chart review of Friedreich's ataxia patients identified those having scoliosis. Demographic data, length of follow-up, brace treatment, operative treatment, and complications were determined. Radiographic review was also performed.

RESULTS:
Seventy-seven patients were identified as having Friedreich's ataxia, of which 49 (63%) were diagnosed with scoliosis. Twenty-seven were male; 22 were female.

Read More: Friedreich's ataxia and scoliosis: the experience at two institutions

Proteomic analysis of hearts from frataxin knockout mice

Marked rearrangement of energy metabolism, a response to cellular stress and altered expression of proteins involved in cell structure, motility and metabolism.

A frequent cause of death in Friedreich's ataxia patients is cardiomyopathy, but the molecular alterations underlying this condition are unknown. We performed 2-DE to characterize the changes in protein expression of hearts using the muscle creatine kinase frataxin conditional knockout (KO) mouse. Pronounced changes in protein expression profile were observed in 9 week-old KO mice with severe cardiomyopathy. In contrast, only several proteins showed altered expression in asymptomatic 4 week-old KO mice. In hearts from frataxin KO mice, components of the iron-dependent complex-I and -II of the mitochondrial electron transport chain and enzymes involved in ATP homeostasis (creatine kinase, adenylate kinase) displayed decreased expression. Interestingly, the KO hearts exhibited increased expression of enzymes involved in the citric acid cycle, catabolism of branched-chain amino acids, ketone body utilization and pyruvate decarboxylation.

Read More: Proteomic analysis of hearts from frataxin knockout mice

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