THE ROLE OF THE MITOCHONDRIAL m-AAA PROTEASE COMPLEX IN THE PATHOGENESIS OF HEREDITARY SPINOCEREBELLAR DEGENERATIONS

This proposal is aimed at investigating the molecular bases and the pathogenic mechanisms which underlie neurodegeneartion in two hereditary disorders of the human nervous system both causing relentlessly progressive disability, a form of spinocerebellar ataxia (ataxia = incoordination of voluntary movements), termed SCA28, and a form of hereditary spastic paraplegia (spastic paraplegia = rigidity of lower limb muscles), named SPG7. The two research groups that propose the project have recently identified the gene (AFG3L2) that causes hereditary ataxia SCA28. These results have allowed to establish that the two disorders, albeit distinct from a clinical standpoint, are due to mutations in two proteins, AFG3L2 and paraplegin, that in mitochondria, the intracellular organelles which represent the “powerhouse” of the cell, are associated within an enzyme complex termed m-AAA. This complex plays an essential role in maintaining the appropriate conformation of many mitochondrial proteins. We expect that this project will provide many important information on this novel disease mechanism that causes degenewration and death of nerve cells. The results we will obtain will allow to answer some questions regarding the selectivity of pathological processes in the brain (for example, why do some neurons degenerate whereas others do not?). Hopefully, the results that will stem from these studies will offer hopes and perspectives for therapy to the patients affected from these relentlessly disabling and rare disorders.