Dr. David Lynch

PI / Investigator: Dr. David Lynch - Children’s Hospital of Philadelphia, PA

Award Type: Award for Innovative Mindset made possible through funding by FARA New Zealand.

Grant Title: The N-terminus of frataxin and its role in FRDA

Lay Summary: Friedreich ataxia (FRDA), the most common recessive ataxia, is characterised by progressive gait and limb ataxia, cerebellar, pyramidal, and dorsal column involvement, optic neuropathy, scoliosis, and cardiomyopathy. The major mutation (96%) causing Friedreich ataxia (FRDA) is an expanded GAA repeat in intron1 of FXN that disrupts transcription of the gene, thereby decreasing production of the protein frataxin.

Frataxin is targeted to mitochondria, where it aids in the synthesis of iron-sulfur (Fe-S) clusters leading to downstream dysfunction of Fe-S-containing enzymes. Such events contribute to mitochondrial failure and diminished ATP production, which create the clinical features of FRDA. Although the details of this pathophysiological cascade are now better defined, the essential components differ little from 20 years ago. Clinical data indicate that frataxin may have other unexplored functions.

One novel approach to understanding FRDA and the functions of frataxin is the investigation of non-GAA mutations rather than GAA expansions, about 4% of FXN mutations. Because such mutations produce similar but not always identical phenotypes to biallelic GAA repeat-FRDA, understanding how such variants cause disease might provide perspective on generalised FRDA mechanisms. Clinically, some specific point mutations produce phenotypes that spare certain features of FRDA but exacerbate others.

The most parsimonious explanation for this is that protein products of such point mutations retain partial biological activity mediated by a region spared in all such mutations, the N-terminus (proximal to amino acid 81) of frataxin; understanding such activities could change portions of the proposed pathophysiology of FRDA. In this proposal, we will use the resources of three labs working on FRDA to investigate the innovative hypothesis that understanding specific point mutations will reveal that alternative functions of the N-terminal portion of FRDA frataxin that play crucial roles in the pathophysiology of FRDA. First, in Aim 1 we will Identify the protein products of FXN non-GAA mutations.

In Aim 2, we will Define the role of the frataxin N-terminus in mediating distinct cellular phenotypes in FRDA cells harboring FXN point mutations or biallelic repeat expansions. In Aim 3, we will define the ability of the N terminus of frataxin to modulate levels of binding partners and their activities in cellular models of FRDA.

Collectively, these aims should quantify the levels and character of the frataxin N-terminus, whether it controls cellular properties in specific ways, and whether it modulates known frataxin binding partners in a manner that participates in the pathophysiology of FRDA.