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[Conformational diseases]
Niels Gregersen1, Peter Bross, Lars A Bolund
1Molekylaer Medicinsk, Forskningsenhed, Arhus Universitetshospital, Skejby Sygehus, 8200 Arhus N.
Abstract:
Conformational diseases are diseases where cellular functions are compromised because of misfolded proteins. The conceptional framework of conformational diseases is found in the cellular protein quality control systems which in the normal and young cell eliminate misfolded proteins. Many inherited genetic defects result in the misfolding of proteins, which may lead to recessive disorders if the proteins in question are totally or partly eliminated or to dominant diseases if the proteins slip through the protein quality control and accumulate in the cell. These inherited diseases are all early onset. Misfolding may also occur in proteins with an intrinsic ability to aggregate and in oxidatively damaged proteins, which accumulate by ageing. If the protein quality control systems are not sufficiently efficient cell toxic protein complexes may accumulate. This pathogenesis is a major contributing factor in the development of late onset neurodegenerative disorders.
Insights
Conformational diseases arise from misfolded proteins, impacting cellular functions. Protein quality control systems normally clear these proteins, but their failure contributes to both early-onset genetic and late-onset neurodegenerative disorders.
Area of Science:
- Biochemistry
- Cell Biology
- Genetics
Context:
- Cellular functions depend on correctly folded proteins.
- Protein quality control (PQC) systems maintain proteostasis by eliminating misfolded proteins.
- Misfolded proteins can arise from genetic defects or aging processes.
Purpose:
- To explain the pathogenesis of conformational diseases.
- To delineate the role of protein misfolding and PQC in disease development.
- To connect protein aggregation to neurodegenerative disorders.
Summary:
- Conformational diseases result from cellular dysfunction due to misfolded proteins.
- Inherited defects can cause early-onset recessive or dominant disorders based on protein clearance.
- Age-related protein aggregation and oxidative damage also contribute to disease.
- Inefficient PQC leads to toxic protein accumulation, driving late-onset neurodegenerative diseases.
Impact:
- Provides a framework for understanding diverse diseases, from genetic disorders to neurodegeneration.
- Highlights the critical role of PQC in preventing disease.
- Offers insights into therapeutic targets for protein misfolding and aggregation disorders.