Molecular mechanisms of protein aggregation and unconventional secretion in the context of inflammation and neurodegenerative disorders

Molecular mechanisms of protein aggregation and unconventional secretion in the context of inflammation and neurodegenerative disorders 2021-2023
Acronym: AggrInflam
Budget: 431.900 RON
Project director: Mari Chiritoiu
External website: full link

This project aims to understand the molecular events associated with protein aggregation and how a Golgi located protein along with the UPR pathway modulate this process. Model proteins such as IL-1β and α-synuclein, previously shown to aggregate will be employed for these studies. Achieving the objectives of this project should facilitate the understanding of the signaling pathways and the sequence of events correlating the stress sensing machinery with cytoplasmic proteome instability.

Background: Inflammation is a hallmark of many pathologies such as autoimmune and neurodegenerative disorders, diabetes and atherosclerosis. Cytokines of the IL-1 family are primary mediators of inflammation. These are cytoplasmic proteins exported from macrophages and monocytes via the unconventional secretory pathway (UPS). I have previously shown that interleukin-1β (IL-1β) secretion form activated primary macrophages is regulated by the GRASP55-IRE1α axis and disrupting this pathway leads to intracellular aggregation of IL-1β, hampers its secretion and causes general proteome instability. 
Hypothesis: Intracellular aggregation of cytoplasmic proteins (such IL-1β, α-synuclein and other) might be correlated with cargo availability for unconventional secretion, therefore modulating this process could provide potential methods to control pathological outcomes for inflammation and neurodegeneration. 
Aim: Dissect the molecular mechanism and identify intracellular factors modulating aggregation and secretion of UPS cargoes. For this purpose we will use as model cargo IL-1β, produced by cells of the immune system and further corroborate the functional conservation of the identified factors for α-synuclein physiology in neurons and C. elegans model for Parkinson’s disease. 
Expected results: This project should facilitate the understanding of signaling pathways and identify the intermediates transducing the information for the stress sensing machinery to induce cytoplasmic proteome instability. Also we estimate to indentify key proteins involved in UPS cargo aggregation, which could be used as targets to control the secretion of cytoplasmic proteins in the context of inflammation and neurodegeneration.

Mari Chiritoiu, PhD
Mari Chiritoiu, PhD

Senior Reseacher III

Mari Chiritoiu graduated from Faculty of Chemistry, University of Bucharest (2004-2008) and received her Ph.D. in Biology from the Institute of Biochemistry of the Romanian Academy in 2014, under the supervision of dr. Stefana Petrescu. She was a posdoctoral fellow in the lab of prof. Vivek Malhotra, at CRG-Centre for Genomic Regulation, Barcelona, Spain (2016-2019) where she investigated the process of unconventional protein secretion using as model cargo the pro-inflammatory cytokine interleukin-1β. In the future, dr. Chiritoiu aims to understand key aspects of the molecular mechanism of leaderless protein export, such as interleukin-1β and α-synuclein, More...

Adriana-Alina Rus, PhD student
Adriana-Alina Rus, PhD student

Adriana-Alina Rus is a researcher in the Institute of Biochemistry of the Romanian Academy. Adriana-Alina is currently working in Molecular Cell Biology in the Molecular Cell Biology.

Cristian Munteanu, Dr.
Cristian Munteanu, Dr.

Research Scientist

ACADEMIC CAREER 2019: Research Scientist (CS) III at the Institute of Biochemistry of the Romanian Academy (IBRA) 2016 – 2019: Research Scientist (CS) at the Institute of Biochemistry of the Romanian Academy (IBRA) 2014 More...

Ioana Militaru, PhD Student
Ioana Militaru, PhD Student

Ioana Militaru is a researcher in the Institute of Biochemistry of the Romanian Academy. Ioana is currently working in Molecular Cell Biology in the Molecular Cell Biology.

Simona Ghenea, Dr.
Simona Ghenea, Dr.

Researcher

Simona Ghenea is a researcher in the Institute of Biochemistry of the Romanian Academy. Simona is currently working in Molecular Cell Biology in the Molecular Cell Biology.