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Assays for the Degradation of Misfolded Proteins in Cells
Published on: August 28, 2016
Functional aspects of cellular microcompartmentation in the development of neurodegeneration: mutation induced
Judit Ovádi1, Ferenc Orosz, Susan Hollán
1Institute of Enzymology, Biological Research Center, Hungarian Academy of Sciences, Budapest, Hungary. ovadi@enzim.hu
Abstract:
Research in the last 10 years has revealed that the development of neurodegeneration is a multistep process during which one or few specific mutant protein species of altered conformation initiate aberrant protein-protein interactions resulting in aggregates forming plaques. This review focuses on the heteroassociations of the mutant proteins with subcellular structures, such as cytoskeleton, cell membranes or with glycolytic enzymes, which may be crucial in the initiation of neurodegeneration such as in Huntington's disease or Alzheimer's disease. Triosephosphate isomerase enzymopathy is a unique glycolytic enzyme deficiency coupled with neurodegeneration. We present data on the mutation induced misfolding process, which likely plays a crucial role in the enhanced associations of the enzyme with the truncated fragment of the isomerase, with the red cell membrane or with the microtubular network. On the basis of our recent clinical and experimental results obtained with two compound heterozygote Hungarian brothers it became obvious that the mutations alone are not sufficient to explain the development of the neurological sympthomes. This underscores the fact that the mutations alone are not enough for the development of the clinical phenotype of a disease.
Insights
Neurodegeneration involves mutant proteins interacting with cellular structures. Specific mutations in triosephosphate isomerase (TPI) linked to neurodegeneration highlight that mutations alone do not cause disease symptoms.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Neurodegeneration is a multistep process initiated by misfolded mutant proteins.
- These proteins form aggregates and interact with cellular components, contributing to disease pathogenesis.
- Diseases like Huntington's and Alzheimer's involve such aberrant protein interactions.
Purpose of the Study:
- To review the role of mutant protein heteroassociations with subcellular structures in neurodegeneration.
- To explore the specific case of triosephosphate isomerase (TPI) enzymopathy, a glycolytic enzyme deficiency linked to neurodegeneration.
- To present experimental data on TPI mutations and their association with cellular components.
Main Methods:
- Literature review on neurodegeneration mechanisms.
- Analysis of mutation-induced misfolding in triosephosphate isomerase.
- Investigation of TPI enzyme associations with cellular structures (e.g., membranes, cytoskeleton).
- Clinical and experimental data analysis from patients with TPI deficiency.
Main Results:
- Mutant proteins initiate neurodegeneration through interactions with cytoskeleton, membranes, and enzymes.
- Triosephosphate isomerase (TPI) deficiency is a unique condition linking glycolytic enzyme defects with neurodegeneration.
- Mutation-induced misfolding of TPI enhances its association with cellular components, including truncated fragments, red cell membranes, and microtubules.
- Clinical data from compound heterozygote patients indicate that mutations alone are insufficient to cause neurological symptoms.
Conclusions:
- Heteroassociations of mutant proteins with subcellular structures are critical in initiating neurodegenerative processes.
- While TPI mutations and misfolding contribute to neurodegeneration, they are not solely responsible for the clinical phenotype.
- The development of neurological symptoms in TPI enzymopathy requires additional factors beyond the genetic mutations themselves.
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