6533b860fe1ef96bd12c34d8

RESEARCH PRODUCT

GENETIC CHAPERONOPATHIES ASSOCIATED WITH GROUP II CHAPERONIN VARIANTS

subject

description

Genetic chaperonopathies manifest themselves from very early in life. Chaperonopathies related to neurodegenerative disorders discussed in “Introduction” section are a heterogeneous group of disorders which affect one or more of the various physiological systems, for example, the nervous system. This heterogeneity is due, in particular, to the not fully known molecular activity, which every single molecular chaperone has within a specific tissue. My general questions about them were 1) why a mutation on a molecular chaperone that is expressed by most, if not all cytotypes, seems to affect the functioning of a single physiological system? 2) why do different mutations on the same molecular chaperone cause apparently different pathologies especially in terms of clinical manifestations? This heterogeneity limits the research approach on diseases, which now is conducted towards every single mutation without being able to generalize a unique molecular process. I spent the first 18 months of my Ph.D. project at the SBARRO Department of Temple University in Philadelphia to study the V98I mutation on chaperone Hsp60 causing hereditary spastic paraplegia (SPG13). For a better understanding of the associated diseases, it would be highly beneficial to examine the impact of mutant chaperone genes during development, starting with fertilization and proceeding throughout the entire ontogenetic process. Zebrafish is amenable to such embryonal analysis as well as studies during adulthood. In addition, the zebrafish genome contains a wide range of genes encoding proteins similar to those that form the chaperoning system in humans. Due to the very complex roles played by Hsp60 in cell and tissue homeostasis, the gene is highly conserved during evolution. Nucleotide and amino acid sequences of Hsp60 in zebrafish have 88% of identity with its human orthologous. The first aim of my research was the establishment of a zebrafish model as an innovative approach for the study of the molecular basis of SPG13 and define the role of missense mutations V98I. In the last 18 months of my Ph.D. project, I was at the BIND Department of the University of Palermo and I had the possibility to study a new mutation that occurred in subunit number 5 of CCT complex. This mutation was found in a pediatric patient who is now being treated by the Department Of Sciences For The Promotion Of Health And Childhood "G. D'Alessandro" at the University of Palermo. Thus, I focused my attention on this novel variant. The main aims were 1) understanding, with the help of bioinformatics software, the type of mutation and if it causes some alteration of chaperonin molecular anatomy; 2) define the morphological changes caused by the mutation in skeletal muscle tissue.