Inclusion bodies

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Inclusion bodies are aggregates of specific types of protein found in neurons, and a number of tissue cells including red blood cells, bacteria, viruses, and plants. Inclusion bodies of aggregations of multiple proteins are also found in muscle cells affected by inclusion body myositis and hereditary inclusion body myopathy. [1]

Contents

Inclusion bodies in neurons may accumulate in the cytoplasm or nucleus, and are associated with many neurodegenerative diseases. [2] Inclusion bodies in neurodegenerative diseases are aggregates of misfolded proteins (aggresomes) and are hallmarks of many of these diseases, including Lewy bodies in dementia with Lewy bodies, and Parkinson's disease, neuroserpin inclusion bodies called Collins bodies in familial encephalopathy with neuroserpin inclusion bodies, [3] inclusion bodies in Huntington's disease, Papp–Lantos bodies in multiple system atrophy, and various inclusion bodies in frontotemporal dementia including Pick bodies. [4] Bunina bodies in motor neurons are a core feature of amyotrophic lateral sclerosis. [5]

Other usual cell inclusions are often temporary inclusions of accumulated proteins, fats, secretory granules, or other insoluble components. [6]

Inclusion bodies are found in bacteria as particles of aggregated protein. They have a higher density than many other cell components but are porous. [7] They typically represent sites of viral multiplication in a bacterium or a eukaryotic cell and usually consist of viral capsid proteins. Inclusion bodies contain very little host protein, ribosomal components, or DNA/RNA fragments. They often almost exclusively contain the over-expressed protein and aggregation and has been reported to be reversible. It has been suggested that inclusion bodies are dynamic structures formed by an unbalanced equilibrium between aggregated and soluble proteins of Escherichia coli . There is a growing body of information indicating that formation of inclusion bodies occurs as a result of intracellular accumulation of partially folded expressed proteins which aggregate through non-covalent hydrophobic or ionic interactions or a combination of both.[ citation needed ]

Composition

Inclusion bodies have a non-unit (single) lipid membrane[ citation needed ]. Protein inclusion bodies are classically thought to contain misfolded protein. However, this has been contested, as green fluorescent protein will sometimes fluoresce in inclusion bodies, which indicates some resemblance of the native structure and researchers have recovered folded protein from inclusion bodies. [8] [9] [10]

Mechanism of formation

When genes from one organism are expressed in another organism the resulting protein sometimes forms inclusion bodies. This is often true when large evolutionary distances are crossed: a cDNA isolated from Eukarya for example, and expressed as a recombinant gene in a prokaryote risks the formation of the inactive aggregates of protein known as inclusion bodies. While the cDNA may properly code for a translatable mRNA, the protein that results will emerge in a foreign microenvironment. This often has fatal effects, especially if the intent of cloning is to produce a biologically active protein. For example, eukaryotic systems for carbohydrate modification and membrane transport are not found in prokaryotes. The internal microenvironment of a prokaryotic cell (pH, osmolarity) may differ from that of the original source of the gene. Mechanisms for folding a protein may also be absent, and hydrophobic residues that normally would remain buried may be exposed and available for interaction with similar exposed sites on other ectopic proteins. Processing systems for the cleavage and removal of internal peptides would also be absent in bacteria. The initial attempts to clone insulin in a bacterium suffered all of these deficits. In addition, the fine controls that may keep the concentration of a protein low will also be missing in a prokaryotic cell, and overexpression can result in filling a cell with ectopic protein that, even if it were properly folded, would precipitate by saturating its environment.[ citation needed ]

In neurons

Inclusion bodies are aggregates of protein associated with many neurodegenerative diseases, accumulated in the cytoplasm or nucleus of neurons. [2] Inclusion bodies of aggregations of multiple proteins are also found in muscle cells affected by inclusion body myositis and hereditary inclusion body myopathy. [1]

Inclusion bodies in neurodegenerative diseases are aggregates of misfolded proteins (aggresomes) and are hallmarks of many of these diseases, including Lewy bodies in Lewy body dementias, and Parkinson's disease, neuroserpin inclusion bodies called Collins bodies in familial encephalopathy with neuroserpin inclusion bodies, inclusion bodies in Huntington's disease, Papp-Lantos inclusions in multiple system atrophy, and various inclusion bodies in frontotemporal dementia including Pick bodies. [4] Bunina bodies in motor neurons are a core feature of amyotrophic lateral sclerosis. [5]

In red blood cells

A red blood cell (erythrocyte) does not usually have inclusions in the cytoplasm, but they may be seen in certain blood disorders.

There are three kinds of red blood cell inclusions:

  1. Developmental organelles
    1. Howell-Jolly bodies: small, round fragments of the nucleus resulting from karyorrhexis or nuclear disintegration of the late reticulocyte and stain reddish-blue with Wright's stain.
    2. Basophilic stipplings – these stipplings are either fine or coarse, deep blue to purple staining inclusion that appear on a dried Wright's stain.
    3. Pappenheimer bodies – are siderotic granules which are small, irregular, dark-staining granules that appear near the periphery of a young erythrocyte in a Wright's stain.
    4. Polychromatophilic red cells – young red blood cells that no longer have nucleus but still contain some RNA.
    5. Cabot rings – ring-like structure and may appear in red blood cells in megaloblastic anemia or in severe anemias, lead poisoning, and in dyserythropoiesis, in which erythrocytes are destroyed before being released from the bone marrow.
  2. Abnormal hemoglobin precipitation
    1. Heinz bodies [11] – round bodies, refractile inclusions not visible on a Wright's stain film. They are best identified by supravital staining with basic dyes.
    2. Hemoglobin H inclusions – alpha thalassemia, greenish-blue inclusion bodies appear in many red blood cells after four drops of blood are incubated with 0.5mL of Brilliant cresyl blue for 20 minutes at 37 °C.
  3. Protozoan inclusion
    1. Malaria
    2. Babesia

In white blood cells

In viruses

Canine distemper virus with cytoplasmic inclusion body (Blood smear, Wright's stain) Canine Distemper Virus Cytoplasmic Inclusion Body (Blood smear, Wright's stain).jpg
Canine distemper virus with cytoplasmic inclusion body (Blood smear, Wright's stain)

Examples of viral inclusion bodies in animals are

Cytoplasmic eosinophilic (acidophilic)-

Nuclear eosinophilic (acidophilic)-

Nuclear basophilic-

Both nuclear and cytoplasmic-

Examples of viral inclusion bodies in plants [13] include aggregations of virus particles (like those for Cucumber mosaic virus [14] ) and aggregations of viral proteins (like the cylindrical inclusions of potyviruses [15] ). Depending on the plant and the plant virus family these inclusions can be found in epidermal cells, mesophyll cells, and stomatal cells when plant tissue is properly stained. [16]

In bacteria

Polyhydroxyalkanoates (PHA) are produced by bacteria as inclusion bodies. The size of PHA granules are limited in E. coli, due to its small size. [17] Bacterial cell's inclusion bodies are not as abundant intracellularly, in comparison to eukaryotic cells.

Polymeric R bodies are found in the bacterial cytoplasm of some taxa, and thought to be involved in toxin delivery. [18]

Isolation of proteins

Between 70% and 80% of recombinant proteins expressed E. coli are contained in inclusion bodies (i.e., protein aggregates). [19] The purification of the expressed proteins from inclusion bodies usually require two main steps: extraction of inclusion bodies from the bacteria followed by the solubilisation of the purified inclusion bodies. Solubilisation of inclusions bodies often involves treatment with denaturing agents, such as urea or guanidine chloride at high concentrations, to de-aggregate the collapsed proteins. Renaturation follows the treatment with denaturing agents and often consists of dialysis and/or use of molecules that promote the refolding of denatured proteins (including chaotopic agents [7] and chaperones). [20]

Pseudo-inclusions

Pseudo-inclusions are invaginations of the cytoplasm into the cell nuclei, which may give the appearance of intranuclear inclusions. They may appear in papillary thyroid carcinoma. [21]

Diseases involving inclusion bodies

DiseaseAffected cells
Inclusion body myositis muscle cells
Amyotrophic lateral sclerosis motor neurons
Dementia with Lewy bodies cerebral neurons

Inclusion body diseases differ from amyloid diseases in that inclusion bodies are necessarily intracellular aggregates of protein, where amyloid can be intracellular or extracellular. Amyloid also necessitates protein polymerization where inclusion bodies do not. [22]

Preventing inclusion bodies in bacteria

Inclusion bodies are often made of denatured aggregates of inactive proteins. Although, the renaturation of inclusion bodies can sometimes lead to the solubilisation and the recovery of active proteins, the process is still very empirical, uncertain and of low efficiency. Several techniques have been developed over the years to prevent the formation of inclusion bodies. These techniques include:

See also

Related Research Articles

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<span class="mw-page-title-main">Phagocyte</span> Cells that ingest harmful matter within the body

Phagocytes are cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are essential for fighting infections and for subsequent immunity. Phagocytes are important throughout the animal kingdom and are highly developed within vertebrates. One litre of human blood contains about six billion phagocytes. They were discovered in 1882 by Ilya Ilyich Mechnikov while he was studying starfish larvae. Mechnikov was awarded the 1908 Nobel Prize in Physiology or Medicine for his discovery. Phagocytes occur in many species; some amoebae behave like macrophage phagocytes, which suggests that phagocytes appeared early in the evolution of life.

<span class="mw-page-title-main">Lewy body</span> Spherical inclusion commonly found in damaged neurons

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References

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  3. ↑ "Encephalopathy, familial, with neuroserpin inclusion bodies (Concept Id: C1858680) – MedGen – NCBI". www.ncbi.nlm.nih.gov. Retrieved 6 April 2021.
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  7. 1 2 Singh SM, Panda AK (1 April 2005). "Solubilization and refolding of bacterial inclusion body proteins". Journal of Bioscience and Bioengineering. 99 (4): 303–310. doi:10.1263/jbb.99.303. PMID   16233795. S2CID   24807019. Inclusion bodies are dense electron-refractile particles of aggregated protein found in both the cytoplasmic and periplasmic spaces of E. coli during high-level expression of heterologous protein. It is generally assumed that high level expression of non-native protein (higher than 2% of cellular protein) and highly hydrophobic protein is more prone to lead to accumulation as inclusion bodies in E. coli. In the case of proteins having disulfide bonds, formation of protein aggregates as inclusion bodies is anticipated since the reducing environment of bacterial cytosol inhibits the formation of disulfide bonds. The diameter of spherical bacterial inclusion bodies varies from 0.5–1.3 μm and the protein aggregates have either an amorphous or paracrystalline nature depending on the localization. Inclusion bodies have higher density (~1.3 mg ml−1) than many of the cellular components, and thus can be easily separated by high-speed centrifugation after cell disruption. Inclusion bodies, despite being dense particles, are highly hydrated and have a porous architecture.
  8. ↑ Umetsu M, Tsumoto K, Nitta S, Adschiri T, Ejima D, Arakawa T, Kumagai I (March 2005). "Nondenaturing solubilization of beta2 microglobulin from inclusion bodies by L-arginine". Biochem Biophys Res Commun. 328 (1): 189–97. doi:10.1016/j.bbrc.2004.12.156. PMID   15670769.
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  11. ↑ Heinz+Bodies at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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  13. ↑ "Plant Viruses Found in Florida and Their Inclusions". University of Florida. Archived from the original on 24 March 2012.{{cite web}}: CS1 maint: unfit URL (link)
  14. ↑ "Inclusions of Cucumber Mosaic Cucumovirus (CMV)". University of Florida. Archived from the original on 19 February 2012.{{cite web}}: CS1 maint: unfit URL (link)
  15. ↑ "Inclusions of Potyviridae Found In Florida". University of Florida. Archived from the original on 19 February 2012.{{cite web}}: CS1 maint: unfit URL (link)
  16. ↑ "Materials and Methods for the Detection of Viral Inclusions". University of Florida. Archived from the original on 19 February 2012.{{cite web}}: CS1 maint: unfit URL (link)
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