Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014;8(5):331-5.
doi: 10.4161/19336896.2014.983398.

Exosome-dependent and independent mechanisms are involved in prion-like transmission of propagated Cu/Zn superoxide dismutase misfolding

Leslie I Grad  1 , Edward Pokrishevsky, Judith M Silverman, Neil R Cashman
Affiliations

Exosome-dependent and independent mechanisms are involved in prion-like transmission of propagated Cu/Zn superoxide dismutase misfolding

Leslie I Grad et al. Prion. 2014.

Abstract

Amyotrophic lateral sclerosis (ALS), a fatal adult-onset degenerative neuromuscular disorder with a poorly defined etiology, progresses in an orderly spatiotemporal manner from one or more foci within the nervous system, reminiscent of prion disease pathology. We have previously shown that misfolded mutant Cu/Zn superoxide dismutase (SOD1), mutation of which is associated with a subset of ALS cases, can induce endogenous wild-type SOD1 misfolding in the intracellular environment in a templating fashion similar to that of misfolded prion protein. Our recent observations further extend the prion paradigm of pathological SOD1 to help explain the intercellular transmission of disease along the neuroaxis. It has been shown that both mutant and misfolded wild-type SOD1 can traverse cell-to-cell either as protein aggregates that are released from dying cells and taken up by neighboring cells via macropinocytosis, or released to the extracellular environment on the surface of exosomes secreted from living cells. Furthermore, once propagation of misfolded wild-type SOD1 has been initiated in human cell culture, it continues over multiple passages of transfer and cell growth. Propagation and transmission of misfolded wild-type SOD1 is therefore a potential mechanism in the systematic progression of ALS pathology.

Keywords: amyotrophic lateral sclerosis; exosome; intercellular transmission; prion-like; protein misfolding; superoxide dismutase.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Propagation and transmission of misfolded SOD1. SOD1 misfolding can be induced by a variety of intracellular and extracellular stresses (1). Once a misfolded template is present, it can induce subsequent cycles of template-directed misfolding, converting neighboring native SOD1 molecules into pathological isoforms, which can subsequently form oligomers and aggregates over time (2). Presumably during the early stages of disease, misfolded SOD1 can also accumulate in the ER-Golgi system by an unknown mechanism (black box), where it can enter the vesicle-mediated secretory pathway, becoming selectively incorporated onto the outer surface of exosomes, exit the cell via secretion (3) and be taken up by neighboring cells. Alternatively, during later stages of disease when neural cells are injured and dying, large proteinaceous aggregates containing misfolded SOD1 are released (4) and subsequently taken up by neighboring cells via macropinocytosis (5). Uptake through this mechanism appears specific making the presence of certain cell surface receptors mediating uptake likely.
Figure 2.
Figure 2.
Generation and actions of misfolded SOD1 inside the cell. Native WTSOD1 or near-native SOD1 mutants are often highly protease resistant making their ability to misfold thermodynamically unfavourable. One explanation is that misfolded SOD1 seed (blue) utilizes post-translational intermediates of WT or mutant that remain partially unfolded and susceptible to induced pathological misfolding. Once populations of misfolded SOD1 (green) accumulate and begin to oligomerize, they become difficult to degrade via the ubiquitin-proteasome system, despite being conjugated with ubiquitin. It is also possible that misfolded SOD1 itself can act as an inhibitor of both the proteasome and autophagic systems, through as yet identified mechanisms, thereby allowing for aberrantly folded protein to elude proteostasis and build up within the cell.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Cleveland DW, Rothstein JD. From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2001; 2:806-19; PMID:11715057; http://dx.doi.org/10.1038/35097565 - DOI - PubMed
    1. Strong M, Rosenfeld J. Amyotrophic lateral sclerosis: a review of current concepts. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4:136-43; PMID:13129799; http://dx.doi.org/10.1080/14660820310011250 - DOI - PubMed
    1. Haverkamp LJ, Appel V, Appel SH. Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction. Brain 1995; 118 (Pt 3):707-19; PMID:7600088; http://dx.doi.org/10.1093/brain/118.3.707 - DOI - PubMed
    1. Robberecht W, Philips T. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 2013; 14:248-64; PMID:23463272; http://dx.doi.org/10.1038/nrn3430 - DOI - PubMed
    1. Stewart H, Rutherford NJ, Briemberg H, Krieger C, Cashman N, Fabros M, Baker M, Fok A, DeJesus-Hernandez M, Eisen A, et al. . Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p. Acta Neuropathol 2012; 123:409-17; PMID:22228244; http://dx.doi.org/10.1007/s00401-011-0937-5 - DOI - PMC - PubMed

Publication types