This document discusses protein misfolding and diseases associated with misfolded proteins. It begins with an introduction to protein folding and reasons why proteins may misfold. Key points include that protein folding is influenced by mutations and external factors. Diseases caused by misfolded proteins are mentioned, such as Alzheimer's and Parkinson's disease. Therapeutic approaches aim to inhibit aggregation, interfere with post-translational changes, and upregulate molecular chaperones. Issues to resolve include developing tools to predict folding effects and determining the balance between protein elimination and accumulation. The conclusion emphasizes ongoing research to understand protein misfolding mechanisms and develop novel therapies.

1. Misfolded protein and disesase associated
with them
Presented by
Y.Naveen Kumar
PI/2021/909
Department of Pharmacoinformatics
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2. Contents
 Introduction
 Importance of Protein folding
 Reasons for protein misfolding
 Energy landscape of protein folding
 Diseses associated with misfolded protein
 Alzheimer's Disease( Beta-Amyloid, and Tau Protein)
 Parkinson's Disease(Lewy Bodies, and Alpha-Synuclein)
 Therapeutic solutions
 Huntington's disease &Proins
 Future issues to be resolved
 Conclusion
 References
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3. Introduction
 Protein folding is the physical process by which a protein chain acquires its native 3-D
structure, a conformation that is usually biologically functional in human body.
 Protein folding by intramolecular forces and passes through intermediates with decreasing
energy and entropy striving toward an energy minimum.
 In vitro, folding intermediates may go off the pathway and use intermolecular forces,resulting
in aggregation.
 In vivo, the folding process is by
molecular chaperones, which shield the proteins
and guide them to the native structure.
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4.  Changes in this structure are consistently associated with loss of function of that protein.
The process by which linear amino acid seuence is converted into its precise 3D structure is a key
issue in molecular biology and is known as protein folding
Importance of protein folding
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5. Reasons for protein misfolding
 A protein is considered to be misfolded if it
cannot achieve its normal native state.
 This can be due to mutations in the amino acid
sequence or a disruption of the normal folding
process by external factors.
 Protein folding is influenced by several
external factors including temperature, pH,
chemicals.
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6. Energy landscape of protein folding
Free-energy folding landscape for
chaperone-mediated protein folding 5
Protein Folding, Misfolding, Aggregation And Amyloid Formation: Mechanisms of A
Oligomer Mediated Toxicities

7. Diseases associated with protein misfolding
 Misfolded proteins include conditions where a protein:
 fails to fold correctly (cystic fibrosis, amyotonic lateral sclerosis)
 is not stable enough to perform its normal function (many forms of cancer)
 forms insoluble aggregates that deposit toxically (neurodegenerative diseases:
Alzheimer’s, Parkinson’s disease, Type II diabetes)
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Protein Folding, Misfolding, Aggregation And Amyloid Formation: Mechanisms of A Oligomer Mediated Toxicities

9. Alzheimer's Disease( Beta-Amyloid and Tau
Protein)
 Most common cause of dementia.
 Tangles of misfolded beta-amyloid proteins
 A second brain protein called tau
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10. Parkinson's Disease(Lewy Bodies, and Alpha-
Synuclein)
 Parkinson's disease is another neurodegenerative condition.
 Parkinson's disease is the appearance of small clumps of misfolded proteins inside neurons in the
substantia nigra.
 The clumps are known as Lewy bodies and are made of a protein called alpha-synuclein
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11. Therapeutic solutions
3 main approaches:
1. Inhibition of protein aggregation.
2. Interference with post-translational peptide
changes before the misfolding/aggregation step.
3. Upregulation of molecular chaperones or
aggregate-clearance mechanisms.
 Current drug research aims at preventing Aβ-
formation
 blocking the formation of amyloid plaques to
slow the progression of the disease.
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Protein Misfolding and Aggregation as a Therapeutic
Target for Polyglutamine Diseases

12. Future issues to be resolved
 To develop quantitative bioinformatic tools(K-fold) to predict the effects of amino acid substitutions
on the folding of a given protein.
 To determine the balance between elimination and accumulation of misfolded proteins, i.e., the
efficiency of protein quality control systems.
 Oxidative cell stress is a common phenomenon in protein misfolding diseases as well as in many
other pathological conditions.
 To elucidate the mechanistic links between accumulated misfolded proteins and mitochondrial
dysfunction, which is the prime cause of oxidative stress.
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13. Conclusion
 Active research ongoing to uncover the mechanisms by which disease-associated proteins misfold,
aggregate,and cause cellular toxicity.
 Continued progress in our ability to interrogate amyloid-forming proteins and their interactions with
other cellular proteins provide confidence that novel therapies will be identified for multiple disease
states.
• Therapeutic options include targeting misfolded protein-chaperone interactions at various points in
the proteostatic pathway,
• promoting protein clearance,
• and large-scale rebalancing
• proteostatic network.
 Identification and in vivo validation of new therapeutic compounds is impeded by the shortage of
known disease drivers and the lack of reliable biomarkers for monitoring therapeutic responses in
relevant animal models.
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14. References
 Gregersen, N., Bross, P., Vang, S. and Christensen, J.H., Protein misfolding and human disease. Annu.
Rev. Genomics Hum. Genet., 2006, 103-124.
 Hartl, F.U., Protein misfolding diseases, Annu. Rev. Biochem, 2017, 86, 21-26.
 Moreno-Gonzalez, I. and Soto, C., July. Misfolded protein aggregates: mechanisms, structures and
potential for disease transmission. Semin. Cell Dev. Biol. ,2011, (Vol. 22, No. 5, 482-487).
 Chaudhuri, T.K. and Paul, S., Protein‐misfolding diseases and chaperone‐based therapeutic
approaches. FEBS J. FEBS J, 273(7), 2006, 1331-1349.
 Sweeney, P., Park, H., Baumann, M., Dunlop, J., Frydman, J., Kopito, R., McCampbell, A., Leblanc,
G., Venkateswaran, A., Nurmi, A. and Hodgson, R.,. Protein misfolding in neurodegenerative diseases:
implications and strategies. Transl. Neurodegener, 6(1), 2017, 1-13.
 Salahuddin, P.,. Protein Folding, misfolding, aggregation and amyloid formation: Mechanisms of Aβ
oligomer mediated toxicities. Biochemistry and Molecular Biology, 1(2),2015 .36-45.
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