Browsing by Author "Lahut, Suna."

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    Parkinson's disease in a large Turkish pedigree with SNCA duplication (PARK4): complexin-1 as a potent biomarker for predictive diagnosis
    (Thesis (Ph.D.)-Bogazici University. Institute for Graduate Studies in Science and Engineering, 2015., 2015.) Lahut, Suna.; Başak, A. Nazlı.; Auburger, Georg.
    Accumulation and aggregation of alpha-synuclein (SNCA) is a hallmark of Parkinson’s disease (PD). Considering the roles of SNCA in both idiopathic and familial PD, we studied blood samples from a large pedigree with SNCA duplication (PARK4), to identify effects of SNCA gain-of-function on expression levels of downstream genes as potential disease biomarkers. Downregulation of complexin-1 (CPLX1) expression level was found to be correlated with PARK4 and also the further investigated cohort with REM sleep behavior disorder (RBD), which resembles presymptomatic PD. In global RNAseq profiling of blood from presymptomatic PARK4, significant upregulations for immune system, lysosome, lipid and platelet activation pathways were detected. The representative genes of upregulated pathways, SPP1, GZMH, and PLTP, were validated in PARK4. However, unlike CPLX1, they failed to distinguish presymptomatic PD from healthy individuals. The longest size variant (allele 2) of the Rep1 repeat region of the SNCA promoter is known to be associated with PD risk. This region was analyzed in idiopathic PD and restless leg syndrome (RLS). Rep1 allele 2 frequency was found significantly decreased in RLS, suggesting reduced SNCA levels contributing to disease. The WW Domain Containing E3 Ubiquitin Protein Ligase (WWP2) mRNA expression level was tested in PARK4 and RBD and was observed to mimic SNCA expression profiles in both cohorts. Western blot analyses of double transfected cells suggested that in the presence of WWP2, SNCA-wildtype, but not SNCA-A53T-mutant, to be degraded.
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    The impact of mutant alsin protein on motor neuron models and the effects of alsin gene knock-down on motor protein genes
    (Thesis (M.S.)-Bogazici University. Institute for Graduate Studies in Science and Engineering, 2011., 2011.) Lahut, Suna.; Başak, A. Nazlı.
    Alsin is a ubiquitously expressed protein with the highest levels in the central nervous system. Mutations in the alsin gene have been associated with several juvenile onset recessive motor neuron diseases. Nine out of 12 reported mutations in the alsin gene are deleterious mutations, leading to premature termination of the protein by an early stop codon; all affected patients are homozygous and all unaffected siblings are heterozygous or normal for the alsin mutations. These together, suggest a loss of function mechanism, responsible for motor neuron degeneration. The aim of this study is to understand the function of alsin using two different approaches. The first approach investigates the effects of mutant alsin on cells with motor neuron characteristics. The alsin mutation generated in this study leads to the truncation of one third of the protein, including the VPS domain, as it is the case in the majority of the natural mutations. The second approach analyzes alsin’s possible interactions with six motor proteins, which have a role in axonal transport: DCTN1, DCTN2, DCTN3, KIF3A, KIF3B and KIF5A. The results of this thesis suggest a rapid degradation of the mutant alsin protein in the NSC34 cells. Thus, it concludes that the pathogenesis of ALS might be due to the overall loss of the alsin protein rather than the loss of the VPS domain, as reported before in the literature. This study also implicates a possible interaction of alsin with three of the six investigated proteins: DCTN1, KIF3A and KIF3B. It further shows a co-localization of alsin and KIF3A in the perinuclear region of N2a cells. This thesis is a first attempt in our laboratory for elucidating the alsin-interacting partners in cell culture systems; we hope that this study will help to pave the ways for understanding the complicated and multilayered functions of the alsin protein.