Disease relevance of Inclusion Bodies

• Identification of VCP as causing IBMPFD has important implications for other inclusion-body diseases, including myopathies, dementias and Paget disease of bone (PDB), as it may define a new common pathological ubiquitin-based pathway [1].
• AHSP-gene-ablated mice exhibit reticulocytosis and abnormal erythrocyte morphology with intracellular inclusion bodies that stain positively for denatured haemoglobins [2].
• Because increased number of inclusion bodies correlates with reduced toxicity, inclusion bodies may protect neurons from alpha-synuclein toxicity [3].
• beta-Amyloid protein immunoreactivity in muscle of patients with inclusion-body myositis [4].
• In addition, the compact structure was observed in vivo in Escherichia coli: inclusion bodies produced upon induction of recA expression in an overproducing strain have a fibrous morphology with the structural parameters of the compact polymer [5].

Psychiatry related information on Inclusion Bodies

• The major pathological feature found in Huntington's disease neurons is the presence of detergent-insoluble ubiquitinated inclusion bodies composed of the huntingtin protein [6].
• Ubiquitin was found as a component of the intermediate filament inclusion bodies characteristic of several major diseases including Lewy bodies of Parkinson's disease, Pick bodies of Pick's disease, Mallory bodies of alcoholic liver disease, cytoplasmic bodies of a specific myopathy, and Rosenthal fibres within astrocytes [7].
• PURPOSE: Aging and oxidative stress resulting from over-expression of Alzheimer precursor protein (betaAPP) have been studied as important factors contributing to the major age-related (sporadic), and minor (hereditary) forms of Alzheimer's disease (AD), and muscle inclusion body myositis, (IBM) [8].

High impact information on Inclusion Bodies

• We previously found that overexpression of human GFAP in astrocytes of transgenic mice is fatal and accompanied by the presence of inclusion bodies indistinguishable from human Rosenthal fibers [9].
• The cartilage matrix from these patients stained poorly with antibody specific for perlecan, but there was staining of intracellular inclusion bodies [10].
• Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human [11].
• Characterization of alpha1-antitrypsin in the inclusion bodies from the liver in alpha 1-antitrypsin deficiency [12].
• On addition of CoQ10 to reconstituted UCP1 from inclusion bodies, fatty-acid-dependent H+ transport reached the same rate as with native UCP1 [13].

Chemical compound and disease context of Inclusion Bodies

• Amiodarone- and desethylamiodarone-induced myelinoid inclusion bodies and toxicity in cultured rat hepatocytes [14].
• The UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene was recently identified as the causative gene for hereditary inclusion body myopathy (HIBM) [15].
• We observed that creation of a stop codon at this ScaI, which causes a COOH-terminal 9-amino acid deletion, results in loss of chloramphenicol resistance and total deposition of the mutant protein in inclusion bodies in Escherichia coli [16].
• NH2-terminal fragments of cPLA2 spanning the C2 domain were expressed as inclusion bodies in Escherichia coli, extracted with solvent to remove phospholipids, and refolded to yield a domain capable of binding phospholipid vesicles in a Ca(2+)-dependent manner [17].
• We previously characterized a defective-folding mutant of maltose-binding protein of Escherichia coli, MalE31, which formed periplasmic inclusion bodies [18].

Biological context of Inclusion Bodies

• While the growth temperature and medium pH had little effect on inclusion body formation, co-overproduction of the dnaKJ operon, but not of the groE operon, suppressed aggregation at the expense of intracellular accumulation [19].
• We show here that genetic reduction of REGgamma has no effect on the well-defined neurological phenotype of R6/2 HD mice and does not affect inclusion body formation in the R6/2 brain [20].
• We have analyzed the sequence of the beta globin gene of a chromosome that is linked to the occurrence of an inclusion body beta-thalassemia characterized in the heterozygote by moderate anemia, severe red cell abnormalities, splenomegaly, inclusion body formation, elevated Hb A2 levels, and an increased in vitro alpha/beta chain synthetic ratio [21].
• Mutations in the valosin-containing protein (VCP) gene on chromosome 9p13-p12 recently have been shown to cause autosomal dominant inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia [22].
• Here, we report the central nervous system autopsy findings in a 55-year-old German patient with inclusion body myopathy and frontotemporal dementia who harbors a heterozygous R155C missense mutation residing in the N-terminal CDC48 domain of VCP, which is involved in ubiquitin binding [22].

Anatomical context of Inclusion Bodies

• Similarly, in untransfected breast HBL100 and lung A549 epithelial cells, TRAIL induced the formation of cytoplasmic inclusions that contained cleaved cytokeratin 18 and colocalized with active endogenous caspase-3 [23].
• As in Alzheimer-disease (AD) brain, vacuolated muscle fibers of inclusion-body myositis (IBM) contain abnormally accumulated beta-amyloid precursor protein (beta APP), including its beta-amyloid protein epitope, and increased beta APP-751 mRNA [24].
• A single-chain Fv construct of the 2B4 T-cell receptor has been made and expressed in Escherichia coli as bacterial inclusion bodies [25].
• Requirement of an intact microtubule cytoskeleton for aggregation and inclusion body formation by a mutant huntingtin fragment [6].
• Fusion of lysosomes to form a giant cytoplasmic inclusion is a major abnormality expressed by multiple hematopoietic and non-hematopoietic cell types in Chediak-Higashi (C-H) patients [26].

Associations of Inclusion Bodies with chemical compounds

• Lipid bodies, nonmembrane-bound cytoplasmic inclusions, serve as repositories of esterified arachidonate and are increased in cells associated with inflammatory reactions [27].
• Unfolding of labeled tetra-Cys CRABP I is accompanied by enhancement of FlAsH fluorescence, which made it possible to determine the free energy of unfolding of this protein by urea titration in cells and to follow in real time the formation of inclusion bodies by a slow-folding, aggregationprone mutant (FlAsH-labeled P39A tetra-Cys CRABP I) [28].
• Inclusion bodies containing beta-lactamase could be refolded at high yields of active protein, even without added GdmHCl [29].
• 2H,15N-labeled tOmpA was produced as inclusion bodies, refolded in detergent solution, trapped with APol A8-35, and the detergent removed by adsorption onto polystyrene beads [30].
• A hallmark of these so-called polyglutamine diseases is the presence of ubiquitylated inclusion bodies, which sequester various components of the 19S and 20S proteasomes [20].

Gene context of Inclusion Bodies

• Both subunits were found mainly in the inclusion body fraction in the bacterial expression strains, and they were solubilized and renatured with the recovery of catalytic (CKA1) and stimulatory (CKB1) activities [31].
• Human UCP2 and 3 expressed in Escherichia coli inclusion bodies are solubilized, and by exchange of sarcosyl against digitonin, nucleotide binding as measured with 2'-O-[5-(dimethylamino)naphthalene-1-sulfonyl]-GTP can be restored [32].
• We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells [33].
• At post-mortem, neurons in the central nervous system of patients have been found to accumulate N-terminal fragments of mutant htt in nuclear and cytoplasmic inclusions [34].
• Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice [35].

Analytical, diagnostic and therapeutic context of Inclusion Bodies

• Neuronal degeneration and Lafora inclusion bodies predate the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures and EEG epileptiform activity [35].
• Electron microscopy of the hepatocytes showed that subtoxic concentrations of propranolol (12.5 to 125 mumol/L) and verapamil (12.5 to 100 mumol/L) induced multilamellar inclusion bodies after 24 hr of incubation [36].
• In addition, evaluation of their airway epithelial cells obtained by bronchoscopy demonstrated that these cells contained inclusion bodies consistent with deposits of ceramide trihexoside, suggesting that part of their functional obstruction to airflow may be secondary to intrinsic airway disease [37].
• We treated eight patients who had inclusion body myositis (IBM) with oral prednisone therapy, and we performed muscle biopsies before and after treatment [38].
• This polypeptide was solubilized from inclusion bodies with 6 M guanidine hydrochloride and purified by metal chelate affinity chromatography [39].

References