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Proteins in Disease Mechanisms


Proteins in Disease Mechanisms

João Vicente / Tiago Cordeiro

Other lecturers
Federico Herrera, Eduardo Melo, Paulo Pereira, Duarte Barral, Paula Leandro, Carlos Cordeiro, Carlos Farinha, Cláudia Almeida, Sandra Tenreiro and Joaquim Ferreira.

Proteins are essential macromolecules in the cell which are involved in a diversity of cellular processes and

functions. However, proteins also play a role in disease through a diversity of mechanisms. This curricular unit will cover different cases in which the multiple roles of proteins in disease processes will be illustrated using examples:

i) proteins as toxic agents (gain of function) or facilitators of disease (protein pathogens); ii) proteins with impaired biological activity (loss of function) or localization (trafficking defects); iii) defects in protein networks (defective interactions); and iv) proteins as facilitators (virulence factors) in disease processes. Methodological and therapeutic perspectives associated with these pathologies will be conveyed. At the end of this curricular unit, students will be expected to understand the role of a particular protein in the broader context of cellular function and dysfunction (disease).


1. Proteins in disease: an overview

Protein misfolding in disease: amyloids (gain of function); activity (loss of function); localization (trafficking defects). Protein homeostasis.

2. Proteins in neurodegenerative amyloid diseases

Amyloid-beta peptide and AD; Transthyretin and FAP; alpha-synuclein and PD. Modulators of protein aggregation and mechanisms. Cellular and organism models.

3. Protein trafficking and sorting defects in Disease

CFTR and Cystic fibrosis. Small molecule therapeutics. Protein Replacement therapy.

4. Metabolic Diseases

Inborn errors of metabolism. Phenylalanine hydroxylase and Phenylketonuria. Pharmacological chaperones.

5. Protein dysfunction in Cancer

6. Proteins as virulent agents

In the tutorial guided group activities, students will have the opportunity to further explore a set of particular aspects of the selected themes starting from the analysis of a research paper, whose discussion will be guided by the lecturer which for e.g. can set broad questions on the paper under analysis to trigger discussion. In these activities the students will select a topic for which, after literature search, they will make a presentation and discussion, which will be the core evaluation tool.

Main Bibliography

  1. Protein Structure and Diseases (2011) R. Donev (Ed) Adv Protein Chemistry and structural biology Vol 83, Academic Press, Elsevier
  2. Protein Folding: An Introduction (2015) Cláudio M. Gomes & Patrícia F.N. Faísca (Eds) SpringerBriefs Series Protein Folding and Structure (Series Editor: Cláudio M. Gomes)Springer International Publishing

Review articles

  1. Chiti F and Dobson CM (2017) “Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade”. Annu Rev Biochem 86: 27-68.
    doi: 10.1146/annurev-biochem-061516-045115
  2. Eisenberg DS and Sawaya MR (2017) “Structural Studies of Amyloid Proteins at the Molecular Level”. Annu Rev Biochem 86:69-95.
    doi: 10.1146/annurev-biochem-061516-045104
  3. Sontag EM et al (2017) “Mechanisms and Functions of Spatial Protein Quality Control”. Annu Rev Biochem 86:97-122.
    doi: 10.1146/annurev-biochem-060815-014616.
  4. Varshavsky A (2017) “The Ubiquitin System, Autophagy, and Regulated Protein Degradation”. Annu Rev Biochem 86:123-128.
    doi: 10.1146/annurev-biochem-061516-044859.
  5. Dikic I (2017) “Proteasomal and Autophagic Degradation Systems”. Annu Rev Biochem 86:193-224.
    doi: 10.1146/annurev-biochem-061516-044908.
  6. Chia S et al (2018) “SAR by kinetics for drug discovery in protein misfolding diseases” PNAS 115 (41): 10245-10250
  7. Gámez A et al (2018) “Protein misfolding diseases: Prospects of pharmacological treatment” Clin Genet 93(3): 450-458.
    doi: 10.1111/cge.13088




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