Gene identification in Hereditary Spastic Paraplegias and characterization of Spastic Paraplegia type 58 (SPG58)

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Dokumentart: PhDThesis
Date: 2016-11
Language: English
Faculty: 4 Medizinische Fakultät
4 Medizinische Fakultät
Department: Medizin
Advisor: Schöls, Ludger (Prof.Dr.)
Day of Oral Examination: 2016-10-14
DDC Classifikation: 500 - Natural sciences and mathematics
610 - Medicine and health
Keywords: Degeneration , Wissenschaft , Querschnittslähmung , Gehirn , Nervenzelle , Kinesin , RNS
Other Keywords: Neurodegeneration
Ribosomal transport
spastic paraplegia
Gene identification
RNA-binding protein
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Hereditary spastic paraplegias (HSPs) are a large group of inherited neurodegenerative disorders characterised by a progressive spasticity and weakness of the lower limbs. Additional symptoms variably occur and define so-called complicated forms of the disease. HSPs exhibit a very high genetic and clinical variability, with at least 84 loci identified and 67 known causative genes. They can be inherited in autosomal dominant, autosomal recessive, and X-linked manner. However, they all share a common trait: a progressive lengthdependent distal axonopathy of the motor neurons that form the corticospinal tracts. The use of whole exome sequencing (WES) has dramatically increased the speed of gene discovery in HSP. This technique granted the conjunct identification of the five genes described here, which are responsible for causing different forms of spastic paraplegia: SPG28, SPG46, SPG26, SPG54 and SPG58. These genes are respectively involved in mitochondrial function, different aspects of lipid metabolism and RNA metabolism. The in-depth study of SPG58 shows how mutations in KIF1C alter the cellular localization of KIF1C protein and affect endogenous protein levels if mutations locate to the ATP-binding domain. This work also elucidates that KIF1C interacts with known RNA-binding proteins (RBPs) and that it also binds RNA directly and is thus itself an RBP. Transcripts bound to KIF1C correspond to genes involved in key mechanisms of cell cycle and gene regulation and in various aspects of RNA metabolism. In addition to the enrichment of ribosomal RNAs, KIF1C also interacts with ribosomal proteins and influences cellular ribosome distribution. This suggests that KIF1C might have a role in the regulation and or transport of ribosomes.

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