Browsing by Author "Mirapalheta, Lorenzo Macedo Correa"
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- Transcriptome profiling in Spinocerebellar ataxia type 2: a focus on RNA-binding proteinsPublication . Mirapalheta, Lorenzo Macedo Correa; Nóbrega, Clévio; Esteves, FilipaSpinocerebellar ataxia type 2 (SCA2) is a rare autosomal dominant neurodegenerative disease first described in 1971 and characterized by cerebellar ataxia and slow saccades. It is caused by a gain-of-function mutation of ATXN2, which encodes the ataxin-2 protein. Ataxin 2 is a multi-functional RNA-binding protein (RBP), and many of its related biological pro cesses, such as calcium homeostasis and lipid metabolism, have been implicated in SCA2 path ophysiology. However, ataxin-2’s RNA-binding function, through which it interacts with vari ous facets of the RNA metabolism system, has yet to be directly linked to SCA2. This thesis’ main objective was to analyze the cerebellar transcriptome of the novel transgenic SCA2 mouse model, TG-SCA-Q129, with a focus on genes encoding RBPs, to un cover whether or not SCA2 might be characterized by a dysfunction of RNA metabolism, as it pertains to its presentation in this mouse model. Eighty-four differentially expressed genes were identified between two lines of trans genic mice compared against wild-type mice, such as Alyref and Aptx, and an analysis of the functions of their encoded RBPs indicated an abundance of functions related to known SCA2 mechanisms, but also to mRNA processing and DNA repair. Gene ontology and weighted gene co-expression network analyses of the whole tran scriptome of the transgenic animals were also conducted, identifying not only known mecha nisms of SCA2, but also inflammation in the cerebellum of the transgenic line with a prominent motor phenotype, and alterations in synaptic vesicle endocytosis. In conclusion, the results from this thesis point to RNA metabolism being a core mech anism in SCA2, and identify DNA repair, pre-mRNA processing, neuroinflammation, and syn aptic vesicle endocytosis as warranting further research to verify whether they might also char acterize SCA2.