Protein Misfolding and Degradation in Genetic Disease


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.

Keywords: folding; protein quality control; degradation; misfolding; aggregation; treatment

Figure 1.

Free‐energy landscape illustrating the conformational space and free energy of a typical protein and the roles of molecular chaperones and proteases of protein quality control systems. For details see text. Reproduced with permission from Gregersen et al. .

Figure 2.

Cartoon illustrating protein folding and misfolding and the interaction of holding, unfolding and folding chaperones and proteases in protein quality control systems. Reproduced with permission from Gregersen et al. .



Akerfelt M, Morimoto RI and Sistonen L (2010) Heat shock factors: integrators of cell stress, development and lifespan. Nature Reviews. Molecular Cell Biology 11(8): 545–555.

Anelli T and Sitia R (2008) Protein quality control in the early secretory pathway. EMBO Journal 27(2): 315–327.

Balch WE, Morimoto RI, Dillin A and Kelly JW (2008) Adapting proteostasis for disease intervention. Science 319(5865): 916–919.

Broadley SA and Hartl FU (2008) Mitochondrial stress signaling: a pathway unfolds. Trends in Cell Biology 18(1): 1–4.

Campioni S, Mannini B, Zampagni M et al. (2010) A causative link between the structure of aberrant protein oligomers and their toxicity. Nature Chemical Biology 6(2): 140–147.

Carrell RW and Lomas DA (1997) Conformational disease. Lancet 350(9071): 134–138.

Chiti F and Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annual Review of Biochemistry 75: 333–366.

Cohen E, Paulsson JF, Blinder P et al. (2009) Reduced IGF‐1 signaling delays age‐associated proteotoxicity in mice. Cell 139(6): 1157–1169.

Cuervo AM (2010) Chaperone‐mediated autophagy: selectivity pays off. Trends in Endocrinology and Metabolism 21(3): 142–150.

Dill KA, Ozkan SB, Shell MS and Weikl TR (2008) The protein folding problem. Annual Review of Biophysics 37: 289–316.

Ellis RJ (2001) Macromolecular crowding: an important but neglected aspect of the intracellular environment. Current Opinion in Structural Biology 11(1): 114–119.

Fernandez‐Funez P, Nino‐Rosales ML, de Gouyon B et al. (2000) Identification of genes that modify ataxin‐1‐induced neurodegeneration. Nature 408(6808): 101–106.

Gersting SW, Lagler FB, Eichinger A et al. (2010) Pahenu1 is a mouse model for tetrahydrobiopterin‐responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo. Human Molecular Genetics 19(10): 2039–2049.

Gregersen N, Andresen BS, Pedersen CB et al. (2008) Mitochondrial fatty acid oxidation defects – remaining challenges. Journal of Inherited Metabolic Disease 31(5): 643–657.

Gregersen N and Bross P (2010) Protein misfolding and cellular stress: an overview. In: Bross P and Gregersen N (eds) Protein Misfolding and Cellular Stress in Disease and Aging, pp. 3–23. New York: Humana Press.

Gregersen N, Bross P, Vang S and Christensen JH (2006) Protein misfolding and human disease. Annual Review of Genomics and Human Genetics 7(1): 103–124.

Hansen JJ, Dürr A, Cournu‐Rebeix I et al. (2002) Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. American Journal of Human Genetics 70(5): 1328–1332.

Henriques BJ, Olsen RK, Bross P and Gomes CM (2010) Emerging roles for riboflavin in functional rescue of mitochondrial beta‐oxidation flavoenzymes. Current Medicinal Chemistry 17(32): 3842–3854.

Hutt D and Balch WE (2010) Cell biology. The proteome in balance. Science 329(5993): 766–767.

Irobi J, Almeida‐Souza L, Asselbergh B et al. (2010) Mutant HSPB8 causes motor neuron‐specific neurite degeneration. Human Molecular Genetics 19(16): 3254–3265.

Kirstein‐Miles J and Morimoto RI (2010) Peptides signal mitochondrial stress. Cell Metabolism 11(3): 177–178.

Leandro P and Gomes CM (2008) Protein misfolding in conformational disorders: rescue of folding defects and chemical chaperoning. Mini Reviews in Medicinal Chemistry 8(9): 901–911.

Li H, Fukuda S, Hasegawa Y et al. (2010) Heat stress deteriorates mitochondrial beta‐oxidation of long‐chain fatty acids in cultured fibroblasts with fatty acid beta‐oxidation disorders. Journal of Chromatography B. Analytical Technologies in the Biomedical and Life Sciences 878(20): 1669–1672.

Magen D, Georgopoulos C, Bross P et al. (2008) Mitochondrial hsp60 chaperonopathy causes an autosomal‐recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy. American Journal of Human Genetics 83(1): 30–42.

Merksamer PI and Papa FR (2010) The UPR and cell fate at a glance. Journal of Cell Science 123(part 7): 1003–1006.

Mijaljica D, Prescott M and Devenish RJ (2010a) Autophagy in disease. Methods in Molecular Biology 648: 79–92.

Mijaljica D, Prescott M and Devenish RJ (2010b) Mitophagy and mitoptosis in disease processes. Methods in Molecular Biology 648: 93–106.

Mu TW, Ong DS, Wang YJ et al. (2008) Chemical and biological approaches synergize to ameliorate protein‐folding diseases. Cell 134(5): 769–781.

Muntau AC and Gersting SW (2010) Phenylketonuria as a model for protein misfolding diseases and for the development of next generation orphan drugs for patients with inborn errors of metabolism. Journal of Inherited Metabolic Disease 33(6): 649–658.

Ng PC and Henikoff S (2005) Predicting the effects of amino acid substitutions on protein function. Annual Review of Genomics and Human Genetics 7: 61–80.

Olsen RK, Olpin SE, Andresen BS et al. (2007) ETFDH mutations as a major cause of riboflavin‐responsive multiple acyl‐CoA dehydrogenation deficiency. Brain 130(part 8): 2045–2054.

Perlmutter D (2010) Alpha‐1 antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver disease‐associated protein aggregates. Annual Review of Medicine [epub ahead of print].

Powers ET, Morimoto RI, Dillin A, Kelly JW and Balch WE (2009) Biological and chemical approaches to diseases of proteostasis deficiency. Annual Review of Biochemistry 78: 959–991.

Qu BH and Thomas PJ (1996) Alteration of the cystic fibrosis transmembrane conductance regulator folding pathway – effects of the Delta F508 mutation on the thermodynamic stability and folding yield of NBD1. The Journal of Biological Chemistry 271(13): 7261–7264.

Rajasekaran NS, Connell P, Christians ES et al. (2007) Human alphaB‐crystallin mutation causes oxido‐reductive stress and protein aggregation cardiomyopathy in mice. Cell 130(3): 427–439.

Rutherford SL and Lindquist S (1998) Hsp90 as a capacitor for morphological evolution. Nature 396(6709): 336–342.

Schapira AH (2008) Mitochondria in the aetiology and pathogenesis of Parkinson's disease. Lancet Neurology 7(1): 97–109.

Schmidt SP, Corydon TJ, Pedersen CB, Bross P and Gregersen N (2010) Misfolding of short‐chain acyl‐CoA dehydrogenase leads to mitochondrial fission and oxidative stress. Molecular Genetics and Metabolism 100(2): 155–162.

Tatsuta T and Langer T (2009) AAA proteases in mitochondria: diverse functions of membrane‐bound proteolytic machines. Research in Microbiology 160(9): 711–717.

Thusberg J and Vihinen M (2009) Pathogenic or not? And if so, then how? Studying the effects of missense mutations using bioinformatics methods. Human Mutation 30(5): 703–714.

Turner GC and Varshavsky A (2000) Detecting and measuring cotranslational protein degradation in vivo. Science 289(5487): 2117–2120.

Voos W (2009) Mitochondrial protein homeostasis: the cooperative roles of chaperones and proteases. Research in Microbiology 160(9): 718–725.

Wang Z and Moult J (2001) SNPs, protein structure, and disease. Human Mutation 17(4): 263–270.

Ward CL and Kopito RR (1994) Intracellular turnover of cystic fibrosis transmembrane conductance regulator. Inefficient processing and rapid degradation of wild‐type and mutant proteins. The Journal of Biological Chemistry 269(41): 25710–25718.

Ward CL, Omura S and Kopito RR (1995) Degradation of CFTR by the ubiquitin‐proteasome pathway. Cell 83(1): 121–127.

Westermark P, Benson MD, Buxbaum JN et al. (2007) A primer of amyloid nomenclature. Amyloid 14(3): 179–183.

Further Reading

Brorsson AC, Kumita JR, MacLeod I et al. (2010) Methods and models in neurodegenerative and systemic protein aggregation diseases. Frontiers in Bioscience 15: 373–396.

Hartl FU and Hayer‐Hartl M (2009) Converging concepts of protein folding in vitro and in vivo. Nature Structural & Molecular Biology 16(6): 574–581.

Luheshi LM and Dobson CM (2009) Bridging the gap: from protein misfolding to protein misfolding diseases. FEBS Letters 583(16): 2581–2586.

Tyedmers J, Mogk A and Bukau B (2010) Cellular strategies for controlling protein aggregation. Nature Reviews. Molecular Cell Biology 11(11): 777–788.

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Bross, Peter, Andresen, Brage S, Corydon, Thomas J, and Gregersen, Niels(Feb 2011) Protein Misfolding and Degradation in Genetic Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006016.pub2]