Accept Cookies?
Provided by OpenGlobal E-commerce

Please wait while your page loads ...

FARAFARA Cure FA

GRP75 overexpression rescues frataxin deficiency and mitochondrial phenotypes in Friedreich Ataxia cellular models

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein crucial for iron-sulphur cluster biogenesis and ATP production. Currently there is no therapy to slow down the progression of FRDA. Recent evidence indicates that posttranslational regulation of residual frataxin levels can rescue some of the functional deficit of FRDA, raising the possibility of enhancing levels of residual frataxin as a treatment for FRDA. Here, we present evidence that mitochondrial molecular chaperone GRP75, also known as mortalin/mthsp70/PBP74, directly interacts with frataxin both in vivo in mouse cortex and in vitro in cortical neurons. Overexpressing GRP75 increases the levels of both wild-type frataxin and clinically relevant missense frataxin variants in HEK293 cells while clinical GRP75 variants such as R126W, A476T and P509S impair the binding of GRP75 with frataxin and the effect of GRP75 on frataxin levels. In addition, GRP75 overexpression rescues frataxin deficiency and abnormal cellular phenotypes such as the abnormal mitochondrial network and decreased ATP levels in FRDA patient-derived cells. The effect of GRP75 on frataxin might be in part mediated by the physical interaction between GRP75 and mitochondrial processing peptidase (MPP), which makes frataxin more accessible to MPP. As GRP75 levels are decreased in multiple cell types of FRDA patients, restoring GRP75 might be effective in treating both typical FRDA patients with two GAA repeat expansions and compound heterozygous patients with point mutations.

Read the entire article HERE

About the Author

Jane Larkindale

SHARE

FacebookTwitterLinkedInYoutube
Event C.jpg

 

Archived in
  Scientific News


 

 

Tagged in
FARA Scientific News


Site Map     Privacy Policy     Service Terms     Log-in     Contact     Charity Navigator