Abstract
In this chapter, we review the diseases caused by misfolding of proteins. The more common proteopathies such as Alzheimer’s disease, Parkinson’s disease, Huntington disease, amyotrophic lateral sclerosis, human prion disease, and muscle dystrophy (and its many forms) are described. Deposits of amyloidosis and tau, which deposit in many proteopathies are characterized and their functions are described.
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Notes
- 1.
Not all conditions involving misfolded proteins are included in the list.
- 2.
Apoptosis is cell self-destruction.
- 3.
Creutzfeldt-Jakob disease is a progressive degeneration of the brain caused by prion (see later in this chapter in the discussion of the prion diseases). The advanced state of this disease is dementia and unsteady physical movements.
- 4.
Cross-β super secondary structure refers to a core of β-pleated strands that are aligned perpendicular to a sheet of regular β-pleated sheets. Secondary structure refers to the packing of one secondary structure adjacent to another structure. For example, a β-pleated sheet adjacent to another β-pleated sheet.
- 5.
The gold standard is the test that has the least false positives and false negatives.
- 6.
The three bilayer nanodiscs were composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dimyristoyl-sn-glycero-3-phospho-(1’-racglycerol) (DMPG) in ratios of 90%/10%, 75%/25%, and 50%/50% (DMPC/DMPG).
- 7.
Although α-synuclein is mostly an IDP it does show some α-helical tendency between residues 6 and 37.
- 8.
The term amyloid means starch-like and derives from Latin amylum (meaning starch) plus the Greek-derived suffix -oid which makes the word an adjective or noun.
- 9.
An oligomer is a complex composed of 2–4 monomers. This contrasts with a polymer where the complex is composed of essentially an unlimited number of monomers.
- 10.
The following nomenclature used in different publications relates to the same substances: C83 = 83-CTFα = CTFα; C99 = 99-CTFβ = CTFβ.
- 11.
Small cleavage product of APP, AICD, and CTFγ are names given in different publications for the same protein.
- 12.
Primer on reading chromosome notation: Example: 14q24.3; 14th- chromosome, q-long arm (p-short arm), 2-band, 4-sub-band, 3-sub-sub-band.
- 13.
Microglial controls immune responses by clearing cellular debris. Astrocytes regulate transmission of electrical impulses in the brain. Both when activated for a prolonged time cause multiple neurotoxic factors such as reactive oxygen species (ROS), essentially free radicals, and their deleterious effects to build up.
- 14.
APOE has three common forms: APOE ε2 is the common gene and may reduce Alzheimer’s disease risk, APOE ε3 has no effect on risk for Alzheimer’s disease, and APOE ε4 increases risk for Alzheimer’s disease.
- 15.
Some simple genetics. One or two copies of the E4 allele increases the risk of coming down with Alzheimer’s disease but that does not mean that the individual carrying the one or two alleles will come down with the disease. Environmental factors play a role and help determine whether the individual will be stricken with the disease. This is the major argument for why individuals should not be tested for the E4 allele; the disease has no cure and having the gene does not predetermine that the person will get the disease.
- 16.
Parthanatos is derived from the Greek word meaning “Death.”
- 17.
The Lewy bodies are seen in surviving neurons.
- 18.
Penetrance is the number of persons who carry the mutated gene and express the affected trait. For example, a person can carry a mutant gene but not express it. Scaling this up, in populations of individuals carrying the same mutant gene 20% may express it.
- 19.
Drp1 is the name given to this protein in humans; in yeast it is called Dnm1.
- 20.
hFis1 is the name given to this protein in humans; in yeast it is called Fis1.
- 21.
Remember familial PD stands for inherited PD and sporadic PD refers to PD that is not inherited.
- 22.
Bulbar refers to a region in the medulla oblongata that controls involuntary movement such as tongue movement.
- 23.
CNBP has also been called zinc finger protein 9 (ZNF9).
- 24.
Introns are usually spliced out of the messenger RNA and are not transcribed.
- 25.
Dumbbell structure refers to two globular regions connected by a long helical section.
- 26.
Hairpin structure refers to two beta strands that look like a hairpin.
- 27.
The sarcolemma is similar to the cell membrane of a cell. It is the “cell membrane” of the striated muscle fiber cell.
- 28.
The sarcoplasm is the cytoplasm of striated muscle cells.
- 29.
Necrosis is cell death caused by enzyme degradation.
- 30.
Cytokines that promote fibrosis.
- 31.
Reinhard JR, Lin S, McKee KK, et al. (2017) Linker proteins restore basement membrane and correct LAMA2-related muscular dystrophy in mice. SciTranslMed:9:eaal4649. doi:10.1126/scitranslmed.aal4649.
- 32.
Humeral refers to the upper arms.
- 33.
The triplet code used is that of the transcribed messenger RNA. If the symbols representing DNA were used the triplet code would be CGC.
- 34.
A review of genetics: Dominant conditions prevail for a disease when only single copy of an abnormal gene is necessary for appearance of the disease. Recessive conditions prevail for a disease when the abnormal gene needs two copies (one from each parent) in order for the disease to occur. Remember penetrance is still important. Low penetrance for a disorder results in the disease not occurring although the genes are present. The person is a carrier of the “bad” gene. A person is a carrier of the gene also if under recessive conditions the person has only one of the genes.
- 35.
Prion originates from Prusiner. It is an acronym for proteinaceous infectious particle.
- 36.
Primary symptom is progressive degeneration of the thalamus. Insomnia, dementia, and appetite loss ensues.
- 37.
Primary symptom is progressive degeneration of the cerebellum. Balance, coordination, muscle tone and equilibrium are affected.
Further Reading
Guo P, Lam SL (2016) Unusual structures of CCTG repeats and their participation in repeat expansion. Bio Mol Concepts: 7(5-6):331. Doi: https://doi.org/10.1515/bmc-2016-0024.
Zhou L, Lu HL. Targeting fibrosis in Duchenne muscular dystrophy. J Neuropath Exp Neurol: 69:771. Doi: https://doi.org/10.1097/NEN.0b013e3181e9a34b.
Holmberg J, Durbeej M. (2013) Laminin-211 in skeletal muscle function. Cell Adhesion Migration:7:111.
Reinhard JR, Lin S, McKee KK, et al. (2017). Linker proteins basement membrane and correct LAMA2-related muscular dystrophy in mice. Sci Transl Med:9:eaal4649. Doi: https://doi.org/10.1126/scitranslmed.aal4649.
Lemmers RJL, van der Vliet PJ, Klooster R, et al. (2010). A unifying genetic model for fascioscapulohumeral muscular dystrophy. Science:329:1650. Doi: https://doi.org/10.1126/science.1189044.
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Abu-Baker A, Messaed C, Laganiere J, et al. (2003) Involvement of the ubiquitin-proteosome pathway and molecular chaperones in oculopharyngeal muscular dystrophy. Hum Mol Genet: 12:2609. Doi: https://doi.org/10.1093/hmg/ddg293.
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Hackman P, Vihola A, Haravuori H, et al.(2002) Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein Titin. Am J Hum Genet:71:492.
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Concha-Marambio L, Pritzkow S., Moda F, et al. (2016). Detection of prions in blood from patients with vatiant Creutzfeldt-Jakob disease. Sci Transl Med:8:370ra183.
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Glossary
- Alzheimer’s disease
-
is caused by misfolded β-amyloid proteins. It is one of the most common proteopathies.
- Amylin
-
is a hormone which is packaged with insulin and secreted from the beta cells in the pancreas.
- Amyloidosis
-
is a condition in which deposits of amyloid are found in various organs.
- Amyotrophic lateral sclerosis (ALS)
-
is a neurodegenerative disease caused by mutations that lead to misfolding of copper-zinc superoxide dismutase 1.
- Becker muscular dystrophy
-
is caused by mutations in the dystrophin gene.
- Congenital muscular dystrophy
-
is caused by mutations in laminin-α2.
- Congo red dye
-
complexes with amyloid to form a substance that exhibits a green birefringence when exposed to polarized light.
- Distal muscular dystrophy
-
is caused by mutations in the dysferlin gene.
- Duchenne muscular dystrophy
-
is caused by a mutation of the dystrophin gene. It is the most common form of muscular dystrophy.
- Emery–Dreyfus muscular dystrophy
-
is caused by mutations in the lamin A/C gene, and emerin gene, syne1 and 2.
Facioscapulohumeral muscular dystrophy
is caused by mutations in the double homeobox 4 gene.
- FAD (familial Alzheimer’s disease)
-
is a rare form of Alzheimer’s disease.
- Fibril
-
is a geometrical shape formed by an amyloid deposit.
- FTD
-
is a comorbid condition to ALS. Comorbid means that the condition occurs with another disease.
- FUS ALS
-
is a protein which when misfolded has symptoms similar to those of ALS especially in that it progresses more slowly than does ALS.
- Human prion diseases
-
are neurodegenerative diseases that are inheritable and are transmitted by misfolded proteins.
- Huntington’s disease
-
refers to a neurodegenerative disease caused by misfolding of huntingtin protein.
- Lewy bodies
-
are cytoplasmic inclusions.
- Limb-girdle muscular dystrophy
-
is the name given to a long list of disorders that is enumerated in the text.
- Misfolding of Synuclein
-
is the cause of Parkinson’s disease (both familial and sporadic).
- Myotonic muscular dystrophy (Steinert’s disease)
-
is a common form of muscular dystrophy.
- Myotonic muscular dystrophy type 1
-
is a form of muscular dystrophy caused by expansion of the repeat region of the dystrophia myotonica protein kinase.
- Myotonic muscular dystrophy type 2
-
is caused by a mutation in nucleic acid-binding protein.
- Oculopharyngeal muscular dystrophy
-
is caused by mutations in the polyadenylate binding protein nuclear 1.
- Parkinson’s disease
-
is the second most common neurodegenerative condition of greater than 65 years of age.
- SAD (sporadic Alzheimer’s disease)
-
is the common form of Alzheimer’s disease.
- Steric Zipper
-
is a geometrical shape taken when amino acid side chains of a β-sheet interdigitates with the side chains of amino acids of an adjacent β-sheet (similar to the teeth of a zipper).
- Synucleopathies
-
are a group of neurodegenerative diseases characterized by fibrillary aggregates of α-synuclein. Misfolding of synuclein is currently believed to be one of the causes of Parkinson’s disease.
- TARDBP
-
is a DNA binding protein which when misfolded by mutation is a cause of Alzheimer’s disease.
- Tau
-
is an intrinsically disordered phosphoprotein used for the formation of microtubules.
- Tau phosphorylation
-
is exhibited in several proteopathies.
- Ubiquilin
-
is a neurogenerative disease caused by mutated ubiquilin.
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Dods, R. (2019). Proteopathies (Proteinopathies). In: Concepts in Bioscience Engineering. Springer, Cham. https://doi.org/10.1007/978-3-030-28303-2_6
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