Protein Misfolding and Degradation in Genetic Disease

Abstract

Molecular disease mechanisms in inherited diseases often spotlight missense mutations that affect the folding process or the stability of the folded structure of proteins. By obstructing the folding process, increasing aggregation or de-stabilising the native structure, disease-associated amino acid replacements may cause loss-of-function or gain-of-function pathologies. For some of this prominent type of mutant proteins, it is possible to improve folding, stabilise the native structure or suppress aggregation using novel approaches. We summarise the mechanistic background for protein misfolding diseases and discuss current concepts for novel therapeutic interventions in this article.

Key Concepts:

• Disease-associated mutations often jeopardise acquisition of the native structure (folding) of the affected protein or destabilise the native structure.

• Protein misfolding leads to full or partial loss-of-function, because the mutant protein is unable or impaired to fold to the native conformation.

• Inefficient removal of misfolded proteins resulting in aggregation may cause a gain-of-function, if aggregates perturb cellular functions.

• Protein misfolding may cause loss-of-function and gain-of-function at the same time with contribution from these two effects being dependent on environmental conditions.

• The steady state levels and residual function of proteins with mutations impairing folding or stability can be modulated by environmental factors and the condition of protein quality control systems.

• Pharmacological chaperones support folding, counteract formation of toxic aggregates or stabilise the native structure of mutant proteins.

• Retuning of the expression of protein quality control components can rescue misfolding of mutant proteins and counteract aggregation.