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Please use this identifier to cite or link to this item: http://hdl.handle.net/2108/963

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contributor.advisorAchsel, Tilmann-
contributor.authorDi Penta, Alessandra-
description19. cicloen
description.abstractSpinal muscular atrophy (SMA) is the most common genetic cause of childhood disease and results from selective loss of α motor neurons. SMA is caused by mutations or deletions of the telomeric copy of the survival motor neuron 1 gene (SMN1). This gene is fundamental for the assembly and regeneration of spliceosomal small nuclear ribonuclear proteins (snRNPs) in all cellular types. The mechanism by which SMN deletion is responsible of selective neuro-muscular defect and specific motor neurons degeneration is still unknown, even if some studies suggested an additional neuronspecific function of the protein. In this work, we investigated in neurons the role of SMN and LSm1 to LSm7, which is involved in mRNA degradation in HeLa cells and may well require the SMN protein for assembly and/or function. We constructed stable neuroblastoma cell lines by RNA interference that express low level of SMN protein and can be considered as a pathological model of SMA. We found that decreased expression of SMN protein does not influence the assembly of snRNPs nor of the LSm1-7 complex. In these cellular clones, LSm1 protein assembles in the cytoplasm as punctuated structures (P-bodies) that are also found in control cells and all other cell types. Moreover, SMN knock-down clones showed an atypical localization of heavy chain neurofilaments (NFH) that fuse in the soma. Overexpressing SMN in wild type neuroblastoma (SH S5Y5) we observed the presence of aggregates in inclusion bodies, suggesting the interaction between SMN and NFH. Even if SMN knock-down resemble the pathological condition of SMA, the level of downregulated protein may be not enough to interfere with the snRNPs biogenesis. We can speculate that in primary culture neurons exists a different regulatory pathway. In fact, experiments on neurons from spinal cord, Purkinje cells and hippocampal neurons demonstrated a mechanism of dendritic localization never seen in cell lines. We showed for the first time that LSm1 protein, beside to localize in P-bodies in the soma, can distribute on the dendrites in punctuate structures that contain no degradation enzymes such as Dcp1a. Further, LSm1 binds specific dendritic mRNAs suggesting an involvement in the mRNA transport and/or in the local protein synthesis. In conclusion, we dimostrated that LSm1 can form new complexes with specific neuronal tasks and hypothesize that the presence of SMN is crucial for the function of these complexes.en
format.extent2294543 bytes-
subjectsnRNPs complexen
subjectLSm1-7 complexen
subjectmRNA transporten
subject.classificationMED/26 Neurologiaen
titleRuolo funzionale e localizzazione sub-cellulare delle proteine Sm e Sm-like nei neuronien
typeDoctoral thesisen
degree.disciplineFacoltà di medicina e chirurgiaen
degree.grantorUniversità degli studi di Roma Tor Vergataen
date.dateofdefenseA.A. 2006/2007en
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