Saygın Bilican

Bio: Saygın Bilican is an academic researcher from University of Cologne. The author has contributed to research in topics: Proteostasis. The author has co-authored 1 publications.

Protein clearance strategies for disease intervention.

Abstract: Protein homeostasis, or proteostasis, is essential for cell function and viability. Unwanted, damaged, misfolded and aggregated proteins are degraded by the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway. Growing evidence indicates that alterations in these major proteolytic mechanisms lead to a demise in proteostasis, contributing to the onset and development of distinct diseases. Indeed, dysregulation of the UPS or autophagy is linked to several neurodegenerative, infectious and inflammatory disorders as well as cancer. Thus, modulation of protein clearance pathways is a promising approach for therapeutics. In this review, we discuss recent findings and open questions on how targeting proteolytic mechanisms could be applied for disease intervention.

CCT2, a newly identified aggrephagy receptor in mammals, specifically mediates the autophagic clearance of solid protein aggregates

Abstract: ABSTRACT Protein aggregates have a strong correlation with the pathogenesis of multiple human pathologies represented by neurodegenerative diseases. One type of selective autophagy, known as aggrephagy, can selectively degrade protein aggregates. A recent study from Ge lab reported the TRiC subunit CCT2 (chaperonin containing TCP1 subunit 2) as the first identified specific aggrephagy receptor in mammals. The switch of CCT2ʹs role from a chaperonin to a specific aggrephagy receptor is achieved by CCT2 monomer formation. CCT2 functions independently of ubiquitin and the TRiC complex to facilitate the autophagic clearance of solid protein aggregates. This study provides the intriguing possibility that CCT2, as a specific aggrephagy receptor, might be an important target for the treatment of various diseases associated with protein aggregation.

Chloroplast protein import determines plant proteostasis and retrograde signaling

Abstract: Proteins containing polyglutamine (polyQ) repeats are prone to aggregation and can lead to distinct human pathologies. For instance, Huntington’s disease is caused by an abnormal expansion of the polyQ stretch (> Q35) of Huntingtin (HTT) protein. However, plants express hundreds of proteins containing polyQ regions, but no pathologies arising from these factors have been reported to date. Here, we ask how plants maintain the proteostasis of polyQ-containing proteins, which are intrinsically enriched in the plant proteomes. To this end, we overexpressed an aggregation-prone fragment of human HTT (Q69) in plant cells. In contrast to invertebrate and mammalian transgenic models, we find that Arabidopsis thaliana plants suppress Q69 aggregation. This elevated proteostasis ability is mediated through the import and degradation of Q69 in chloroplasts. Conversely, inhibition of chloroplast protein import either genetically or pharmacologically reduces the capacity of plant cells to prevent Q69 aggregation. We find that Q69 interacts with the chloroplast stromal processing peptidase (SPP). Notably, expression of synthetic Arabidopsis SPP is sufficient to suppress aggregation of polyQ-expanded HTT in human cells. Beyond ectopically expressed Q69-HTT, endogenous polyQ-containing proteins also aggregate in Arabidopsis upon inhibition of chloroplast import. Among them, the plastid casein kinase 2 (pCK2), which contains a polyQ region next to the chloroplast targeting sequence motif, can also be localized into the nucleus. Upon inhibition of chloroplast import, pCK2 accumulates at higher levels in the nucleus and forms diamond-shaped amyloid-like fibrils surrounding the chloroplasts. These results indicate that the differential conformation and redistribution of pCK2 to the nucleus depends on chloroplast import efficiency, providing a role of polyQ repeats in chloroplast to nucleus communication (i.e. retrograde signaling). Together, our findings establish chloroplast protein import and proteases as determinants of polyQ proteostasis, with important implications for plant biology that can also lead to therapeutic approaches for human diseases that involve protein aggregation.

UCHL1 and Proteasome in Blood Serum in Relation to Dietary Habits, Concentration of Selected Antioxidant Minerals and Total Antioxidant Status among Patients with Alzheimer’s Disease

Abstract: Alzheimer’s disease (AD) is an incurable neurodegenerative disease. It is the most common form of dementia among the elderly population. So far, no effective methods of its treatment have been found. Research to better understand the mechanism of pathology may provide new methods for early diagnosis. This, in turn, could enable early intervention that could slow or halt disease progression and improve patients’ quality of life. Therefore, minimally invasive markers, including serum-based markers, are being sought to improve the diagnosis of AD. One of the important markers may be the concentration of UCHL1 and the proteasome in the blood serum. Their concentration can be affected by many factors, including eating habits. This study was conducted in 110 patients with early or moderate AD, with a mean age of 78.0 ± 8.1 years. The patients were under the care of the Podlasie Center of Psychogeriatrics and the Department of Neurology (Medical University of Białystok, Poland). The control group consisted of 60 healthy volunteers, matched for gender and age. The concentration of UCHL1 and the 20S proteasome subunit were measured by surface plasmon resonance imaging (SPRI). In addition, a nutritional interview was conducted with patients with AD, which assessed the frequency of consumption of 36 groups of products. In the group of patients with AD, compared to the control group, we showed a significantly higher concentration of UCHL1 (56.05 vs. 7.98 ng/mL) and the proteasome (13.02 vs. 5.72 µg/mL). Moreover, we found a low negative correlation between UCHL1 and the proteasome in the control group, and positive in the AD group. The analysis of eating habits showed that the consumption of selected groups of products may affect the concentration of the tested components, and therefore may have a protective effect on AD.

Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

Abstract: There are hundreds of central nervous system (CNS) diseases, but there are few diseases for which the etiology or pathogenesis is understood as well as those of other organ-specific diseases. Cells in the CNS are selectively protected from external and internal insults by the blood-brain barrier. Thus, the neuroimmune system, including microglia and immune proteins, might control external or internal insults that the adaptive immune system cannot control or mitigate. The pathologic findings differ by disease and show a state of inflammation that reflects the relationship between etiological or inflammation-inducing substances and corresponding immune reactions. Current immunological concepts about infectious diseases and infection-associated immune-mediated diseases, including those in the CNS, can only partly explain the pathophysiology of disease because they are based on the idea that host cell injury is caused by pathogens. Because every disease involves etiological or triggering substances for disease-onset, the protein-homeostasis-system (PHS) hypothesis proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances. In this article, I propose a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer's disease, and genetic diseases, through the PHS hypothesis.