Differing Gene Activity Seen in Two Key Cells Derived From Patient

Study helps explain how frataxin's loss affects neurologic, cardiac symptoms of FA

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by Steve Bryson, PhD |

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Nerve and heart muscle cells derived from a man with Friedreich’s ataxia (FA) showed differences in the activity of multiple genes, a study reported.

In nerve cells, deficiency in the frataxin protein, the underlying cause of FA, influenced genes related to energy-producing glucose metabolism, or glycolysis. In heart muscle, changes were evident in genes related to the extracellular matrix — a three-dimensional meshwork of molecules, such as collagen, outside cells that provides structural support.

“Genes involved in glycolysis seem to have an essential role in the neurological aspect of [FA], whereas genes related to the extracellular matrix are fundamental for the development of cardiac disease,” the researchers wrote.

Because central nerve cells rely almost exclusively on energy generated from glucose, problems with related gene activity in FA nerve cells “may explain why the earliest manifestation of the disease is usually neurological,” they added.

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Study into how frataxin loss affects gene activity in key cells

The cell-based study, “Frataxin deficiency alters gene expression in Friedreich ataxia derived IPSC-neurons and cardiomyocytes,” was published in the journal Molecular Genetics & Genomic Medicine.

FA is caused by mutations in the FXN gene, which encodes instructions for frataxin, a protein essential for the proper functioning of energy-producing mitochondria within cells. Such mutations lead to a frataxin deficiency, disrupting energy production, particularly in cells with high-energy demands, including those of the nerves and muscles.

Neurological symptoms of FA typically appear first, including the hallmark loss of balance and coordination (ataxia). About 60% of patients also develop progressive cardiac disease, such as irregular heartbeats (arrhythmias) or hypertrophic cardiomyopathy, the thickening and enlargement of heart muscles.

However, heart involvement in FA is variable; in some cases, it precedes neurological impairment, while in others, heart disease never appears. This suggests different underlying mechanisms and cell-type susceptibility to frataxin deficiency. Despite multiple proposals for the exact function of frataxin, none thoroughly explained why its lack leads to such variable involvement.

Scientists at the University of South Florida examined nerve cells (neurons) and heart muscle cells (cardiomyocytes) derived from an FA patient to investigate the early molecular processes due to frataxin deficiency.

Blood cells were collected from a 34-year-old man diagnosed with FA at age 8, whose first heart symptoms appeared 20 years later and were considered mild and early stage. These blood cells were reprogrammed back into a type of stem cell, then transformed into neurons and heart muscle cells. Tests confirmed reduced FXN activity in both cell types.

To study the role of frataxin deficiency, the team artificially enhanced frataxin activity by infecting FA-derived cells using a harmless lentivirus carrying a functional copy of the FXN gene.

Genetic analysis revealed 127 genes in patient-derived neurons with altered activity, or differentially expressed, compared to control cells. Among them, 37 genes had higher activity (upregulated), and 90 showed lower activity (downregulated). In heart muscle cells, 417 genes were differentially expressed, including 320 upregulated and 97 downregulated genes.

In patient-derived neurons, the most significant biological processes associated with changes in gene expression were related to carbohydrate metabolism, including glycolysis, breaking down glucose to produce energy, and the generation of ATP, the main form of chemical energy used by cells.

In comparison, differentially expressed genes found in patient-derived heart muscle cells were related to the processes and components of the extracellular matrix.

Cardiac fibrosis, or scarring of heart tissue, which occurs due to impairment of the extracellular matrix, has been found in FA patients before the onset of heart disease, the researchers noted.

Finally, differentially expressed genes found in both types of patient-derived cells were normalized with the artificial expression of frataxin, meaning that “frataxin deficiency is likely playing a role in these processes,” they wrote.

Differences between the two cell types “may offer insights into unique effects and susceptibilities of the [neurons] and the heart” in Friedreich’s ataxia, the scientists concluded. Heart and nerve cells “differ significantly in their energy sources and susceptibility to nutrient deprivation.”