Hereditary Ataxia: A Focus on Heme Metabolism and Fe-S Cluster Biogenesis.

Deborah Chiabrando,Francesca Bertino,Emanuela Tolosano

doi:10.3390/ijms21113760

Deborah Chiabrando, Francesca Bertino + Show 1 more

Open Access

https://doi.org/10.3390/ijms21113760

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Abstract

Heme and Fe-S clusters regulate a plethora of essential biological processes ranging from cellular respiration and cell metabolism to the maintenance of genome integrity. Mutations in genes involved in heme metabolism and Fe-S cluster biogenesis cause different forms of ataxia, like posterior column ataxia and retinitis pigmentosa (PCARP), Friedreich’s ataxia (FRDA) and X-linked sideroblastic anemia with ataxia (XLSA/A). Despite great efforts in the elucidation of the molecular pathogenesis of these disorders several important questions still remain to be addressed. Starting with an overview of the biology of heme metabolism and Fe-S cluster biogenesis, the review discusses recent progress in the understanding of the molecular pathogenesis of PCARP, FRDA and XLSA/A, and highlights future line of research in the field. A better comprehension of the mechanisms leading to the degeneration of neural circuity responsible for balance and coordinated movement will be crucial for the therapeutic management of these patients.

Highlights

Balance and coordinated movements of the body are the result of a complex neuronal network involving the basal ganglia, cerebellum and cerebral cortex as well as peripheral motor and sensory pathways
The present review focuses exclusively on those forms of hereditary ataxias caused by mutations in genes involved in heme metabolism or Fe-S cluster biogenesis (Table 1), the two major iron consuming processes in the cell
The aim of this review is to provide a detailed description of the biology of heme metabolism and Fe-S cluster biogenesis with a focus on the possible altered molecular mechanisms at the basis of ataxia

Summary

Introduction

Balance and coordinated movements of the body are the result of a complex neuronal network involving the basal ganglia, cerebellum and cerebral cortex as well as peripheral motor and sensory pathways. A wide range of mutations have been described in different genes resulting in the alteration of distinct mechanisms as mitochondrial function, oxidative stress, DNA repair, protein folding, cytoskeletal proteins, heme metabolism and iron–sulfur [Fe-S] cluster biogenesis [1]. The present review focuses exclusively on those forms of hereditary ataxias caused by mutations in genes involved in heme metabolism or Fe-S cluster biogenesis (Table 1), the two major iron consuming processes in the cell. Despite recent progresses in elucidating the role of Fe-S clusters in the maintenance of the neuronal networks at the basis of coordination and balance, less is known about the role of heme in these processes. The aim of this review is to provide a detailed description of the biology of heme metabolism and Fe-S cluster biogenesis with a focus on the possible altered molecular mechanisms at the basis of ataxia. Large sensory neuronsPosterior columns of spinal cordDentate nucleus of cerebellum Cerebellum

Heme Metabolism and Fe-S Cluster Biogenesis

Therapeutic Approaches

Findings

Concluding Remarks