Friedreich ataxia (FRDA) is a rare, progressive autosomal recessive neurodegenerative disease characterized by progressive gait and limb ataxia; cerebellar, pyramidal, and dorsal column involvement; visual defects; scoliosis; and cardiomyopathy. FRDA is caused by transcriptional silencing of the frataxin gene and consequential deficiency of frataxin, a mitochondrial protein crucial for iron–sulphur cluster biogenesis and adenosine triphosphate (ATP) production. ATP stores and transports chemical energy within cells. Currently, no therapy is available to slow down the progression of FRDA.
Researchers in Department of Pediatrics and Division of Neurology at Children’s Hospital of Philadelphia and the University of Pennsylvania have found that mitochondrial molecular chaperone GRP75 is a major post-translational regulator of frataxin level and function. Overexpression of GRP75 rescues frataxin deficiency and abnormal cellular phenotypes such as mitochondrial fragmentation and ATP deficit — both in typical FRDA patients with homozygous GAA repeat expansions and compound heterozygous patients with point mutations.
Why it matters:
Restoration of frataxin levels in FRDA patients represents a major strategy for the treatment of FRDA. Most studies focus on enhancing frataxin gene expression using vector-based gene delivery; however, less is known about the residual frataxin protein that critically affects disease onset and progression. By identifying GRP75 as an upstream regulator of frataxin protein, the study provides a new avenue to increase frataxin bioavailability and function. More importantly, GRP75 overexpression has more prominent effect on clinically relevant missense frataxin variants, which are found in compound heterozygote patients and in general lead to lower frataxin levels because of reduced protein stability and mitochondrial import. Targeting GRP75 might be more beneficial for FRDA patients with frataxin variants, who make up about 4 percent of the FRDA population.
Who conducted the study:
A team of Department of Pediatrics and Neurology researchers at CHOP and Penn conducted the study, led by Yi Na Dong, PhD, a research associate, and David R. Lynch, MD, PhD, the principal investigator who co-directs the Friedreich Ataxia Center of Excellence.
How they did it:
The team used cellular and molecular approaches to identify the binding partners of frataxin and found that GRP75 physically interacts with frataxin. With this information in hand, the researchers further investigated the functional interaction between frataxin and GRP75 in both heterologous system and FRDA cellular models.
“We hope that these results will propel FRDA researchers to probe for GRP75 as a component of therapeutic pathways to be targeted in FRDA, as GRP75 reduction observed in multiples cell types of FRDA could lead to further decreases in frataxin level and function and worsening of symptoms,” wrote the researchers in a paper published in December.
While the findings are promising, a GRP75-based orally administered drug is still lacking. The effect of GRP75 is driven by its ATPase activity and substrate binding. Identifying molecular determinants that potentiates GRP75 ATPase activity and substrate binding is crucial for developing effective therapeutic compounds. The research team now plans to investigate the binding sites between GRP75 and frataxin in an effort to develop orally administered compounds.
Where the study was published:
The study was published in Human Molecular Genetics.