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Review
. 2016 Jun;100(3):426-33.
doi: 10.1016/j.yexmp.2016.03.010. Epub 2016 Apr 9.

The mechanisms of Mallory-Denk body formation are similar to the formation of aggresomes in Alzheimer's disease and other neurodegenerative disorders

S W French  1 , A S Mendoza  1 , Y Peng  1
Affiliations
Review

The mechanisms of Mallory-Denk body formation are similar to the formation of aggresomes in Alzheimer's disease and other neurodegenerative disorders

S W French et al. Exp Mol Pathol. 2016 Jun.

Abstract

There is a possibility that the aggresomes that form in the brain in neurodegenerative diseases like Alzheimer's disease (AD) and in the liver where aggresomes like Mallory-Denk Bodies (MDB) form, share mechanisms. MDBs can be prevented by feeding mice sadenosylmethionine (SAMe) or betaine. Possibly these proteins could prevent AD. We compared the literature on MDBs and AD pathogenesis, which include roles played by p62, ubiquitin UBB +1, HSPs70, 90, 104, FAT10, NEDD8, VCP/97, and the protein quality control mechanisms including the 26s proteasome, the IPOD and JUNQ and autophagosome pathways.

Keywords: 26S proteasome; Neurofibrillary tangles (NFT); Protein quality control; β amyloid (Aβ).

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Figures

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Fig. 4. NAIP was up-regulated in AH livers
A. Immunohistochemical analysis of liver biopsies obtained from two representative patients with alcoholic hepatitis and two representative control patients. The specimens were stained for the presence of NAIP (green, the first column) and ubiquitin (red, the second column). There was no co-localization seen with the tri-color filter (the third column). The fourth column demonstrated the fluorescence intensity measurement of NAIP stain. Screen snips were obtained from the morphometric screen to visualize and compare the intensity of staining in MDB forming hepatocytes, neighboring non-MDB forming cells, and control cells. The fluorescence intensity was traced along the yellow line in the top picture and shown as a green tracer in the bottom picture. B) Fluorescent intensity bar graph of MDB forming hepatocytes, non-MDB forming hepatocytes, and control cells from three AH specimens and three control specimens. The results were shown as Mean ± S.D.. The comparisons showing statistical significance (p<0.01) were indicated.
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Fig. 5
Autophagy, the ER-associated degradation (ERAD) pathway, the JUxta Nuclear Quality (JUNQ) control compartment, and the Insoluble Protein Deposit (IPOD) systems are cellular mechanisms responsible for protein maintenance. These systems are dependent on many chaperones and transport proteins for successful protein management. Mca1, Hsp104, Hsp40, Ydj1, Ssa1, VCP/p97, and p62 are some of the important chaperones in protein quality control systems. Most misfolded/aggregated proteins are initially processed in the ERAD and autophagy systems. The chaperones are very active in these protein quality control systems. But once proteins become terminally aggregated, the IPOD and JUNQ systems are utilized by the cell as alternate pathways for damage control. The upregulation of Mca1, Hsp104, Ydj1, p62, Ssa1, Hsp40 and VCP/p97 in ASH may indicate that autophagy, the ERAD, the JUNQ, and the IPOD systems are active in ASH.
See this image and copyright information in PMC

References

    1. Amidi F, French BA, Chung D, Halsted CH, Medici V, French SW. M-30 and 4HNE are sequestered aggresomes in the same hepatocyte. Exp Mol Pathol. 2007;83:296–300. - PMC - PubMed
    1. Bardag-Gorce F, Francis T, Nan L, Li J, Lu YH, French BA, French SW. Modifications in p62 occur due to proteasome inhibition in alcoholic liver disease. Life Sci. 2005;77:2594–2602. - PubMed
    1. Bardag-Gorce F, French BA, Nan L, Song H, Nguyen SK, Yong H, Dede J, French SW. CYP2E1 induced by ethanol causes oxidative stress, proteasomes inhibition and cytokeratin aggresome (Mallory body-like) formation. Exp Mol Pathol. 2006;81:191–201. - PubMed
    1. Bardag-Gorce F, Oliva J, Li J, French BA, French SW. SAMe presents the induction of the immunoproteasme and preserves the 26S proteasome in the DDC-induced MDB mouse model. Exp Mol Pathol. 2010;88:353–362. - PMC - PubMed
    1. Bardag-Gorce F, Riley N, Nguyen RO, Montgomery RO, French BA, Li J, van Leeuwen FW, Lungo W, McPhaul LW, French SW. The mechanism of cytokeratin aggresome formation: the role of mutant ubiquitin (UBB+1) Exp Mol Pathol. 2003;74:160–167. - PubMed

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