The Role of Mitochondria in Cerebellar Ataxias

Cerebellar ataxias (CAs) are a group of heterogeneous disorders clinically characterized by lack of motor coordination. CAs can be caused by acute structural cerebellar damage or by progressive cerebellar degeneration, usually linked to an underlining genetic metabolic disorder. CAs due to genetic alterations, also referred as primary CAs (PCAs), are usually progressive neurodegenerative disorders with increased disability along the disease course. Because PCAs usually affect young adults and impair motor and cognitive function, the impact on quality of life is substantial. Primary CAs are very heterogeneous in clinical presentation, disease progression and pathophysiology. Because of the variegate mechanisms behind cerebellar degeneration, up today, no definite disease-modifying therapies are available. The main therapeutic strategies are based on rehabilitation and symptomatic approaches.Central Nervous System (CNS) has a very high energy demand, and in particular Purkinje cells (PC). PC, in fact, are among the largest and more arborized cells in the CNS, requiring an elevated amount of metabolic energy to function properly. It is therefore evident that any perturbation in cell energy metabolism can have a huge impact on PC function and survival. Cell energy largely depends on the production of Adenosine Triphosphate (ATP). ATP can be synthesized by two main pathways, the anaerobic glycolysis that is rapid but less efficient, and the oxidative phosphorylation (OXPHOS) that requires more time but yield a large amount of ATP. OXPHOS reactions take place in the mitochondria. Taking into account these principles, it is quite clear that cerebellar function and mitochondria activity are extremely interconnected. And in fact, ataxia is one of the most frequent symptoms of mitochondrial disease. In most cases, it occurs in the context of multi-systemic presentation. Mitochondrial disease with predominant ataxia phenotype can be related to a variety of genes defect that ranges from mutations in mitochondrial DNA (mtDNA) to defect in nuclear genes important for mtDNA maintenance. During my PhD program, my work has been focused on studying the role of mitochondrial physiology in the development of cerebellar ataxia, with a particular attention to disorders linked to a deficiency in Coenzyme Q10. During my thesis, inherited and degenerative cerebellar ataxias will be briefly discussed. The main part of the text will be centred on the disorders that I directly investigated during the course of my research and that led to peer review publications. In particular, I will discuss the role of mitochondrial dysfunction in autosomal recessive cerebellar ataxias due to mutations in ANO10, ADCK3, and ACO2. Moreover, I will present functional studies proving the link between Ataxia with Oculomotor Apraxia type 1 (AOA1) and mitochondria. Finally, the role of CoQ10 deficiency in Multi-systemic atrophy will be described.