Cerebellar compartmentation of prion pathogenesis

Abstract

In prion diseases, the brain lesion profile is influenced by the prion "strain" properties, the invasion route to the brain, and still unknown host cell-specific parameters. To gain insight into those endogenous factors, we analyzed the histopathological alterations induced by distinct prion strains in the mouse cerebellum. We show that 22L and ME7 scrapie prion proteins (PrP , PrP ), but not bovine spongiform encephalopathy PrP , accumulate in a reproducible parasagittal banding pattern in the cerebellar cortex of infected mice. Such banding pattern of PrP aggregation did not depend on the neuroinvasion route, but coincided with the parasagittal compartmentation of the cerebellum mostly defined by the expression of zebrins, such as aldolase C and the excitatory amino acid transporter 4, in Purkinje cells. We provide evidence that Purkinje cells display a differential, subtype-specific vulnerability to 22L prions with zebrin-expressing Purkinje cells being more resistant to prion toxicity, while in stripes where PrP accumulated most zebrin-deficient Purkinje cells are lost and spongiosis accentuated. In addition, in PrP stripes, enhanced reactive astrocyte processes associated with microglia activation support interdependent events between the topographic pattern of Purkinje cell death, reactive gliosis and PrP accumulation. Finally, we find that in preclinically-ill mice prion infection promotes at the membrane of astrocytes enveloping Purkinje cell excitatory synapses, upregulation of tumor necrosis factor-α receptor type 1 (TNFR1), a key mediator of the neuroinflammation process. These overall data show that Purkinje cell sensitivity to prion insult is locally restricted by the parasagittal compartmentation of the cerebellum, and that perisynaptic astrocytes may contribute to prion pathogenesis through prion-induced TNFR1 upregulation.

Re-transmissibility of mouse-adapted ME7 scrapie strain to ovine PrP transgenic mice

“…Spongiform degeneration is known to be one of the hallmarks of neurodegeneration in prion disease [8]. To examine the extent of spongiform degeneration in ME7-infected TgSShpPrP brain tissue, using immunohistochemistry staining, hippocampal regions of control and infected mice brains were subjected to hematoxylin and eosin (H&E) staining.…”

“…3A). In prion diseases, the brain region profile is influenced by the prion's ‘strain properties,’ which indicate the invasion route to the brain [8]. We analyzed the histopathological alteration induced by the ME7 scrapie strain in the whole brain regions of TgSShpPrP mice.…”

Insights into cerebellar development and connectivity

“…In lurcher ( Lc/+ ), gain of function of the δ2 glutamate receptor causes the developmental restriction of a zebrin II expression domain at the CZ/PZ boundary (Tano et al, 1992), and the weaver mutation induces a Purkinje cell ectopia that is primarily restricted to the CZ (Eisenman et al, 1998; Armstrong and Hawkes, 2001). Strikingly, there are a growing number of disease-related genetic mutations and insults that manifest as stripes, ranging from disease mutations of the Niemann Pick type C gene to viral infection and the spreading of prions (Sarna and Hawkes, 2003; Armstrong et al, 2010; Stromme et al, 2011; Williams et al, 2007; Ragagnin et al, 2017). In all cases, the Purkinje cells that are degenerating in stripes typically conform, as expected, to either the zebrin II+ or the zebrin II- subset.…”

Recent advances on the molecular pathogenesis of prion diseases

“…In Kuru, spread of the disease occurred from the ingestion of prion‐infected, dead relatives as part of mourning practices, whereas in chronic wasting disease, prions may be transmitted not only through ingesting prion‐contaminated food, but also by exposure to a prion‐contaminated environment . In all instances, prions hold structural properties that cause different disease presentations, which can be passed on to another individuals . However, the most common form of human prion disease, sporadic Creutzfeldt‐Jakob disease, is not caused by exposure to infectious prions but occurs as a rare disease from unknown causes .…”