Morales R, Estrada LD, Diaz-Espinoza R, Morales-Scheihing D, Jara MC, Castilla J, Soto C.
Molecular cross talk between misfolded proteins in animal models of Alzheimer's and prion diseases.
J Neurosci. 2010 Mar 31;30(13):4528-35.
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The observation that the pathogenesis of neurodegeneration in an animal model of AD is accelerated by prion infection (and vice versa) is very interesting, and the authors consider three possible mechanisms that could underlie this effect. First, they consider that both agents could independently impair clearance mechanisms resulting in some sort of additivity. Second, a variant of the first, they consider the possibility that each agent could independently damage different cellular targets that would give rise to an exacerbation of either single effect. Finally, they consider a cross-seeding mechanism whereby aggregates of Aβ promote the aggregation of PrP and vice versa. They cite published evidence reporting that similar cross-seeding phenomena have been previously observed in vitro (with different proteins). Cross-seeding has also been inferred from studies of interactions between prions in yeast. Although evidence in this Morales study supports the possibility of cross-seeding between PrP and Aβ in vitro, with pure proteins, the evidence that cross-seeding actually occurs in vivo is very indirect—and the extent to which it contributes to the phenotypic interaction between the mouse models remains speculative. Refreshingly, the authors do not overstate their case for cross-seeding. The observed colocalization of both proteins to the same inclusion bodies, while consistent with a direct interaction required for cross-seeding, is rather weak evidence for direct physical interaction. Proteins can readily be incorporated into the same inclusion bodies without any direct physical interaction (see Rajan et al., 2001). There is clearly a large gap between the in vivo and in vitro data in this paper that still needs to be filled in.
There is a fourth possibility that should also be considered in thinking about these interesting observations. The type of interaction reported in this paper brings to mind the recent work from the Morimoto lab, which demonstrates, using C. elegans, genetic interactions between unrelated folding-defective and aggregation-prone proteins. They have shown that expression of polyglutamine-containing proteins harboring pathogenic-length, aggregation-prone polyQ tracts elicits a mutant phenotype of temperature-sensitive (ts) alleles of unrelated genes—at permissive temperatures (Gidalevitz et al., 2006). They also report the converse effect—that the presence of ts alleles exacerbates the phenotype of aggregation-prone polyQ proteins. Similar genetic interactions have been reported in worms harboring ALS-linked mutant SOD1 transgenes (Gidalevitz et al., 2009). These interactions can be reconciled in a model whereby aggregation-prone proteins compete with other clients of molecular chaperones that are required to both facilitate protein folding and to suppress protein aggregation. According to this view, it is not the aggregate per se that is toxic to cells. It is, rather, the tendency to aggregate or—more precisely—it is the preoccupation of cells’ anti-aggregation machinery (sometimes referred to as the proteostasis network) with persistently expressed, highly aggregation-prone proteins that ultimately results in a "collapse" of the cells’ proteostasis system.
Rajan RS, Illing ME, Bence NF, Kopito RR.
Specificity in intracellular protein aggregation and inclusion body formation.
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Gidalevitz T, Ben-Zvi A, Ho KH, Brignull HR, Morimoto RI.
Progressive disruption of cellular protein folding in models of polyglutamine diseases.
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Gidalevitz T, Krupinski T, Garcia S, Morimoto RI.
Destabilizing protein polymorphisms in the genetic background direct phenotypic expression of mutant SOD1 toxicity.
PLoS Genet. 2009 Mar;5(3):e1000399.
A number of proteopathies coexist in the aging human brain, but whether these diseases arise independently or in pathogenic concert remains unclear. In this paper, Morales and colleagues present a reasonably compelling argument that aggregated Aβ and PrPSc can cross-seed the misfolding and aggregation of each other in vitro and in an animal model of Aβ amyloidosis, arguing for a closer look at the epidemiology of these two pathologies in humans. Lewy body disease and Alzheimer disease overlap in a significant proportion of cases; might similar cross-talk be operable for prion disease and Alzheimer disease? Evidence for such an interaction in humans remains limited, but Morales and colleagues note several supportive studies. I would add the intriguing case of a 28-year-old man who contracted Creutzfeldt-Jakob disease from a dural graft performed in childhood, and who also had a remarkably heavy load of senile plaques and cerebral β amyloid angiopathy at death at age 28 (see Preusser et al., 2006). Though it is possible that the Aβ lesions arose independently in this instance, for example, as a result of the trauma to the brain, the findings of Morales and colleagues suggest that a potential pathogenic interaction of PrP and Aβ should also be considered. More studies, both in humans and models, clearly are needed.
On a technical note, it would be useful to know the sex of the mice used in the Morales study. Female Tg2576 mice develop more and earlier Aβ deposition than do males, so an imbalance of males and females in the PrPSc-treated group and the control group could yield spurious differences. It will also be interesting in future studies to examine the effects of seeding with Aβ-rich extracts in PrP-transgenic mice. As the authors note, there are numerous mechanistic questions yet to be addressed, but this nice paper should stimulate further experiments in the rapidly evolving field of protein conformational diseases.
Preusser M, Ströbel T, Gelpi E, Eiler M, Broessner G, Schmutzhard E, Budka H.
Alzheimer-type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt-Jakob disease after dural grafting.
J Neurol Neurosurg Psychiatry. 2006 Mar;77(3):413-6.
I agree with the comments posted by Ron Kopito and Lary Walker. I would add a couple of additional caveats. The in vivo work did not involve large numbers of animals, and the differences in survival rates could potentially be influenced by small sample size (in addition to gender, as Lary mentioned). Likewise, the inoculation protocol did not really include the best negative controls, which would be either brain lysates of sick mice depleted of prion protein, or brain lysates from animals that express PrP, but have not yet developed pathology. The in vitro elements of the paper are crucial to determining whether PrP can directly seed Aβ aggregation. Along those lines, it would be very nice to know whether brain lysates exhibit seeding capacity that is dependent on either Aβ or PrP aggregates within the lysate. At the end of the day, this paper provides a lot of exciting food for thought, and, along with other papers that show cross-seeding phenomena in neurodegeneration, should inspire much further experimentation.
A recent study by Ghoshal and her colleagues may be of interest here. In this study, the authors reported that numerous Aβ plaques were co-distributed with spongiform degeneration.
Ghoshal N, Cali I, Perrin RJ, Josephson SA, Sun N, Gambetti P, Morris JC.
Codistribution of amyloid beta plaques and spongiform degeneration in familial Creutzfeldt-Jakob disease with the E200K-129M haplotype.
Arch Neurol. 2009 Oct;66(10):1240-6.
The discussion about pathogenic interactions between different amyloidogenic proteins and their aggregates should also consider the possibility that one of these proteins might play a special role in amyloidopathic degenerative diseases and act as a pivotal amplifier of amyloid toxicity. Aβ has been shown to interact with aggregates of several other amyloidogenic proteins, and those aggregates might develop some of their effects through interaction with Aβ and mechanisms of Aβ toxicity, in particular, via the neurotrophin receptor p75 (see the Aβ-crosslinker-hypothesis). These mechanisms may be common to many amyloidopathic degenerative diseases, and partly account for the observed blending of such diseases.