The role of proteasomal complexes in the neurodegenerative Huntington’s disease

A tétel rövid nézete
dc.contributor.advisorTar, Krisztina
dc.contributor.authorAladdin, Azzam
dc.contributor.authorvariantAladdin, Azzam
dc.contributor.departmentMolekuláris orvostudomány doktori iskolahu
dc.contributor.submitterdepDE--Általános Orvostudományi Kar -- Orvosi Vegytani Intézet
dc.date.accessioned2021-09-03T08:25:51Z
dc.date.available2021-09-03T08:25:51Z
dc.date.created2021hu_HU
dc.date.defended2021-09-07
dc.description.abstractSeveral neurodegenerative disorders are characterized by impairment protein degradation in neuronal cells. Ineffective clearance of misfolded proteins by the proteolytic pathways leads to the accumulation of toxic protein oligomers and aggregates in neuron cells. The dysregulation of ubiquitin-dependent and ubiquitin-independent proteasome activities plays an integral role in neurodegenerative diseases including Huntington’s disease. However, the precise role of proteasomal complexes in HD pathogenesis in extraneuronal tissues is not fully understood. Here we show that the ubiquitin-proteasome system responds to mutant huntingtin (Htt) in juvenile HD fibroblasts to protects cells. Moreover, the Blm10/PA200 activator family promotes the proteasomal degradation of N terminal Htt (N-Htt) fragments by a ubiquitin-independent pathway. In the first study, we determined the crosstalk between mitochondria and the ubiquitin-proteasome system in juvenile HD fibroblasts. We found increased mitochondrial reactive oxygen species, and this increase is accompanied by a significant increase in the mitochondrial membrane potential. Moreover, mitochondrial oxidative phosphorylation does not reveal significant differences compared to control. Mitochondria function is controlled by the fission-fusion machinery. Thus, we measured the fission-fusion proteins. We found that fusion proteins are lower, this decrease leads to reduced mitochondria branching in diseased cells. We found also that juvenile HD fibroblasts are viable and both apoptosis and necrosis are relatively low similar to healthy control. On other hand, we demonstrated higher 26S proteasomal activity, which is associated with elevated Parkin in gene expression and protein level. Furthermore, we determined accelerated proteasomal degradation of Mfn1 the mitochondrial fusion protein, which leads to reduced mitochondrial fusion. We suggest that juvenile HD fibroblasts respond to mutant Htt to balance mitochondrial structural loss by promoting proteasomal activity to protect cells. In the second project, we determined the role of the Blm10/PA200 activator family in the proteasomal degradation of N-Htt fragments in a ubiquitin-independent manner. We conducted this part of our study using a combination of yeast and human HD models. We found that the deletion/depletion of the Blm10/PA200 family in the HD model drive to elevated mutant N-Htt aggregates formation and cellular toxicity. Moreover, the proteasomal activator Blm10/PA200 family interacts with soluble N-Htt fragments. The Blm10/PA200 family also promotes the activity of proteasome and accelerates the degradation of soluble N-Htt in vitro. Overall, our results demonstrate how the ubiquitin-proteasome system responds to mutant Htt, by enhancing the proteasomal degradation of specific Parkin substrates to protect the cells. Besides, the Blm10/PA200 activator family promotes the proteasomal degradation of toxic N-Htt fragments in a ubiquitin-independent manner. This activity leads to reduced aggregates formation and cellular toxicity. Here, we determined the value of enhancing the activity of the proteasomes by proteasomal activators. This activity may have the advantage to restore mitochondrial function and reduce the accumulation of toxic Htt species to attenuate cellular toxicity in HD.hu_HU
dc.format.extent114hu_HU
dc.identifier.urihttp://hdl.handle.net/2437/321556
dc.language.isoenhu_HU
dc.subjectHuntington’s disease (HD)hu_HU
dc.subjectMitochondriahu_HU
dc.subjectBlm10/PA200hu_HU
dc.subject.disciplineElméleti orvostudományokhu
dc.subject.sciencefieldOrvostudományokhu
dc.titleThe role of proteasomal complexes in the neurodegenerative Huntington’s diseasehu_HU
dc.title.translatedThe role of proteasomal complexes in the neurodegenerative Huntington’s diseasehu_HU
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