PrPScaccumulation in neuronal plasma membranes links Notch-1 activation to dendritic degeneration in prion diseases
© DeArmond and Bajsarowicz; licensee BioMed Central Ltd. 2010
Received: 24 July 2009
Accepted: 21 January 2010
Published: 21 January 2010
Prion diseases are disorders of protein conformation in which PrPC, the normal cellular conformer, is converted to an abnormal, protease-resistant conformer rPrPSc. Approximately 80% of rPrPSc accumulates in neuronal plasma membranes where it changes their physical properties and profoundly affects membrane functions. In this review we explain how rPrPSc is transported along axons to presynaptic boutons and how we envision the conversion of PrPC to rPrPSc in the postsynaptic membrane. This information is a prerequisite to the second half of this review in which we present evidence that rPrPSc accumulation in synaptic regions links Notch-1 signaling with the dendritic degeneration. The hypothesis that the Notch-1 intracellular domain, NICD, is involved in prion disease was tested by treating prion-infected mice with the γ-secretase inhibitor (GSI) LY411575, with quinacrine (Qa), and with the combination of GSI + Qa. Surprisingly, treatment with GSI alone markedly decreased NICD but did not prevent dendritic degeneration. Qa alone produced near normal dendritic trees. The combined GSI + Qa treatment resulted in a richer dendritic tree than in controls. We speculate that treatment with GSI alone inhibited both stimulators and inhibitors of dendritic growth. With the combined GSI + Qa treatment, Qa modulated the effect of GSI perhaps by destabilizing membrane rafts. GSI + Qa decreased PrPSc in the neocortex and the hippocampus by 95%, but only by 50% in the thalamus where disease was begun by intrathalamic inoculation of prions. The results of this study indicate that GSI + Qa work synergistically to prevent dendrite degeneration and to block formation of PrPSc.
Despite major advances in understanding prion biology and the conversion of PrPC to PrPSc, the mechanisms of early synaptic degeneration have remained largely unknown until now. In this review we show that accumulation of the abnormal prion protein (PrPSc) in neuronal plasma membranes during prion diseases directly affects the processing of γ-secretase complex substrates and cause early dendritic degeneration.
The prion diseases in humans include sporadic Creutzfeldt-Jakob disease (sCJD), familial CJD (fCJD), and variant CJD (vCJD), the last acquired by ingestion of bovine spongiform encephalopathy (BSE)-contaminated food. Other human prion diseases include a thalamic variant of CJD called sporadic and familial fatal insomnia; kuru, acquired by ritualistic cannibalism in aborigines of New Guinea; and Gerstmann-Sträussler-Scheinker syndrome, a rare familial form of cerebral PrP amyloidosis. In animals, the main prion diseases include scrapie in sheep, which can be transmitted to rodents as laboratory scrapie; BSE in cattle; and chronic wasting disease in deer and elk.
Prion diseases are disorders of protein conformation in which PrPC, the normal cellular conformer, is converted to an abnormal, protease-resistant conformer named PrPSc. PrPSc was first described in scrapie-infected Syrian hamsters in 1982 . By convention, the abnormal prion protein is designated PrPSc in all prion diseases. sCJD is the most common prion disease, accounting for ~85% of the total human prion cases. In sCJD, spontaneous conversion of PrPC to PrPSc begins the process of sustained conversion of PrPC to PrPSc. In fCJD, disease is caused by mutations of the prion protein gene (PRNP) . Fewer than 1% of CJD cases are acquired by infection with exogenous prions such as prion-contaminated human growth hormone preparations, human dura mater grafts, corneal transplants, and BSE contaminated food products. In all cases of laboratory scrapie, disease is begun by inoculation with prions, usually injected unilaterally into the thalamus. As a general rule, the prions that are used in the laboratory are obtained from a 1:10 dilution of homogenized scrapie-infected mouse or hamster brain. In animals, injection of synthetic PrPSc manufactured in E. coli also produce disease verifying that PrPSc protein is the sole component of prions [3, 4].
Plasma membrane dysfunction and degeneration occur very early in prion diseases, before the defining neuropathological change of vacuolar degeneration of gray matter. This vacuolation (spongiform degeneration) is an intermediate step in the morphological progression of prion disease and it precedes nerve cell death, which is a late morphological change. The importance of the plasma membrane in prion diseases is emphasized by the following data. More than 80% of the abnormal prion protein, PrPSc, accumulates in the plasma membrane [5, 6]. Many of the signs and symptoms of prion diseases are caused by dysfunction and degeneration of specialized portions of the membrane such as synapses [5, 7, 8]. The importance of plasma membrane degeneration in disorders such as CJD, kuru and scrapie was first recognized by the late Peter Lampert in 1969 [9, 10]. Using electron microscopy, he found multiple foci of neuronal membrane degeneration and no defining viral particles. Therefore, he proposed that the plasma membrane is the main target of these diseases. Twelve years later, Stanley Prusiner found that the scrapie agent is composed of a single, abnormal, protease-resistant mammalian protein, the prion protein (PrP), and devoid of nucleic acid . He named this unusual agent a "prion" and the mammalian protein that comprises the prion, PrPSc. In this article, we review the evidence that PrPSc accumulates in high concentration in membrane rafts, activates Notch-1 signaling and, in doing so, promotes neuronal dendritic degeneration.
Exponential increase of PrPSc
Prion diseases are disorders of protein conformation. The normal cellular form of the protein, PrPC, is expressed constitutively at high levels in neurons and at low levels in glial cells . PrPC appears to be neuroprotective and protease sensitive. It's C-terminal half contains 3α-helices, A, B and C and it is attached to the outer leaf of the plasma membrane by a glycolipid anchor. The N-terminal half is largely unstructured. Like many glycolipid-anchored proteins, a high concentration of PrPC is found in membrane rafts . In CJD and scrapie, a protease resistant form of PrP accumulates, PrPSc. It is believed that in PrPSc a large β-helix forms in the middle of the PrPC molecule eliminating all of α-helix A and a portion of α-helix B . PrPSc causes neurodegeneration. Multiple variations in a host animal's amino acid sequence of PrPSc, variations in the β-structure imposed on PrPSc, and differences in oligomerization of PrPSc determine the incubation time of the disease, the neuroanatomical distribution of vacuolar degeneration and the host species barrier that classically define prion strains .
How does the abnormal prion protein propagate? Fred Cohen suggested a model for the conversion of PrPC to PrPSc in which he showed that when PrPC is exposed to PrPSc it acquires an identical beta structure as PrPSc . The process is not reversible. The conversion of the structure from α-helix to β-helix, or in some cases to a β-sheet is efficient, rapid and leads to an exponential increase in PrPSc.
PrPScaccumulates early in plasma membranes
The kinetics of PrPSc accumulation in subcellular fractions was measured during the course of scrapie in the thalamus and neocortex of Syrian hamsters inoculated unilaterally in the thalamus with the Sc237 strain of scrapie prions. The incubation time, defined as the time required to develop clinical signs of scrapie, is ~65 days in this model. Plasma membrane, endosomes and lysosomes were enriched in Percoll gradients and identified with specific markers . The separation of subcellular fractions was accurate since plasma membrane, early and late endosomal, and lysosomal markers were highly enriched in the respective fractions. For example, Na-K ATPase was greatly enriched in plasma membrane fractions in control and scrapie infected Syrian hamsters. Endosomal fractions contained only ~20% of that found in membrane fractions, and none was found in lysosomes . The volume and total protein of each fraction were monitored throughout the separation procedure in order to calculate the total Proteinase K (PK) resistant PrPSc in each fraction. A conformation-dependent immunoassay (CDI) was used to measure the amount of PrP27-30, the PK resistant peptide of PrPSc, in the samples [16, 17]. The CDI uses sodium-magnesium phosphotungstate to specifically precipitate PrPSc and separate it from PrPC. About 87 amino acids are removed from the N-terminal and a small portion of the C-terminal of PrPSc (32-35 kD) by PK digestion to yield the PrP27-30 peptide. The experiment described below was performed before we understood that ~50% of PrPSc in a Syrian hamster inoculated with Sc237 prions is PK sensitive (sPrPSc) . Evidence indicates that sPrPSc converts PrPC to protease resistant PrPSc (rPrPSc). Nevertheless, most of the evidence indicates that rPrPSc causes the neurological dysfunction and neurodegeneration in prion diseases, as we shall describe in this review.
We focused on the early synaptic dysfunction and degeneration because these changes produce clinical symptoms and because it may be possible to intervene with drug therapy at this stage of the disease. Late-occurring neuronal death may be treatable with compounds that influence autophagy [27, 29]. It should be noted that most CJD patients die at an intermediate stage of disease with vacuolization and little or no detectable nerve cell loss .
rPrPScis transported from one brain region to another by axonal transport
This evidence suggests a very slow axonal transport system requiring ~4 weeks to travel 3-5 mm and precludes any of the active transport systems, which take only hours to days. We believe PrPSc diffuses passively along the axon membranes, driven by a concentration gradient that is higher near the cell body in the thalamus and is progressively lower towards neocortex . Alternatively, as rPrPSc diffuses into axons it may convert adjacent axonal PrPC molecules into sPrPSc or rPrPSc resulting in the continuous conversion process that eventually reaches presynaptic boutons.
Axonal terminals and transynaptic conversion of PrPC to PrPSc
To examine PrPSc accumulation in the presynaptic boutons we prepared synaptosomes from the neocortex of Syrian hamsters at 70 dpi. Synaptosomes, which contain presynaptic boutons and postsynaptic membranes, were stained for rPrPSc (green) and synaptophysin (red)  (Fig. 5). Synaptophysin is one of the specific markers for synaptic vesicles in presynaptic boutons. rPrPSc appears to be on the surface of the synaptosomes as well as in the interior (Fig. 5). The majority of the objects in the figure were also immunostained for synaptophysin as seen in the merged image (Fig. 5). The similarity of the immunohistochemistry for PrPSc and synaptophysin suggest that some PrPSc is located within the axon terminals. Not all of the PrPSc positive structures were synaptophysin positive. They probably represent fragments of plasma membrane contaminants.
The conversion of PrPC to PrPSc begins in the postsynaptic membrane and continues to be formed in the postsynaptic neurons by one of two possible mechanisms: degeneration of the presynaptic bouton [5, 21] or release of PrPSc during synaptic transmission. Once it traverses the synaptic cleft, it can bind to PrPC on the postsynaptic membrane and convert it to rPrPSc, possibly in endosomes by endocytosis of PrPC-PrPSc complex.
Dendritic degeneration occurs early in prion disease
Notch-1 signaling in prion diseases
During embryonic development of the central nervous system, regressive changes in dendrites are regulated by a Notch-1 signaling pathway [36, 37]. Activation of Notch-1 stimulates the HES and HERP families of inhibitor effecter proteins , which in turn inhibit pro-neuronal genes that maintain the length and branching of dendrites. During development, ligands such as Delta-like and Jagged expressed on adjacent cells lead to the truncation of Notch-1 . The truncated Notch-1 is a specific ligand for Nicastrin, which is 1 of the 4 proteins that comprise γ-secretase complex. Nicastrin carries the truncated Notch-1 into the γ-secretase complex where it cleaves off the active molecule called the Notch-1 intracellular domain, NICD [40, 41]. NICD is translocated to neuronal nuclei where it activates the HES and HERP genes that inhibit the expression of pro-neuronal genes that maintain dendrites. We speculated that if this pathway were active in prion disease, we might find increased amounts of NICD and perhaps changes in the γ-secretase complex itself.
Cholesterol rich membrane rafts: Hypothesis
In normal control brains PrPC, Notch-1 and γ-secretase are concentrated in membrane rafts . Similarly, in prion infected brains PrPSc (sPrPSc and/or rPrPSc), Notch-1 and γ-secretase are concentrated in membrane rafts. How then does PrPSc lead to formation of NICD? We can only guess at this time. The data suggest that PrPSc causes truncation of Notch-1 in a dose dependent manner, probably without participation of Delta-like or Jagged ligands. Nicastrin transports the truncated Notch-1 to the γ-secretase complex. From these data we propose a null hypothesis that inhibition of NICD formation during prions disease will prevent dendritic degeneration. As we shall see, this hypothesis fails to account for the complexity of γ-secretase functions.
We obtained γ-secretase inhibitor (GSI) LY411575 from Drs. Todd Golde and Pritam Das at the Mayo Clinic, Jacksonville, Florida. This is a particularly potent Notch-1 inhibitor. Like many GSI's designed to treat Alzheimer's disease, it produces severe gastrointestinal tract and immune system toxicity; therefore, it is not used clinically. However, we believed it could be used for preclinical proof of concept studies. We also planned to combine quinacrine (Qa) with GSI because Qa was found to clear all PrPSc from scrapie-infected ScN2a cells within 5 days . It was our belief that any reduction of PrPSc in brain caused by Qa would be additive to the GSI effect in terms of reducing NICD formation and dendrite degeneration.
Wild type CD1 mice were inoculated in the thalamus with RML prions. Oral doses of GSI alone (5 mg/kg/day), Qa alone (40 mg/kg/day) and combined GSI + Qa (same doses) were prepared in a nutritional chocolate drink containing 0.007% DMSO. The treatment was started at 50 dpi when disease was well established in the thalamus and had just begun to spread to the neocortex. Because of GSI toxicity, continuous treatment had to be terminated after 43 to 55 days.
Effect of treatment on dendrites
Control mice normally express a small amount of NICD (Fig. 10A). In the dendrite load versus NICD level plot, control NICD levels are associated with abundant dendrites indicating a balance between stimulators and inhibitors (Fig. 10B). In the untreated RML infected mice, a 3 to 4 fold increase of NICD was associated with a marked reduction in the dendrite load as seen in the graph. This suggests that prion infection shifted the balance toward inhibition. GSI alone was associated with a very low NICD level, as expected, but dendritic trees showed no recovery (Fig. 9), which argues that GSI inhibited both γ-secretase stimulators and inhibitors of dendritic growth. Combined GSI + Qa treatment resulted in an almost normal NICD level and a greater than control dendritic arborization (Fig. 10). This suggests that Qa was able to modulate the effect of GSI. Qa "destabilizes" membrane rafts by redistributing cholesterol from the plasma membrane to endosomes and lysosomes . We speculate that perhaps Qa also separates PrPSc from Notch-1 or separates components of the γ-secretase complex from each other. Qa alone doubled NICD levels compared to controls and was associated with a near normal dendritic load (Fig. 10). To accomplish this, Qa must have also proportionately increased the stimulators of dendritic growth. The data demonstrate that GSI + Qa work synergistically to regulate the maintenance of dendrite size and shape in prion disease. Furthermore, these data argue that the γ-secretase complex plays a major role in the early dendritic changes.
GSI + Qa treatment decreases rPrPSc
Residual rPrPScin white matter can restart the disease
In this review we focused on the exponential accumulation of rPrPSc in the plasma membrane of neurons and how it causes regressive changes in dendrites. We did not review the additional evidence from our laboratory that rPrPSc was associated with decreased evoked release of neurotransmitters from neocortical synaptosomal preparations during scrapie in Syrian hamsters and that it was associated with presynaptic bouton degeneration . In other experiments, accumulation of rPrPSc in membranes in mouse scrapie decreased binding of specific ligands to receptors on the postsynaptic membrane [49, 50]. Accumulation of rPrPSc in the plasma membrane of a scrapie-infected N2a cell line (ScN2a) was found to decrease membrane fluidity by 7-fold compared to uninfected N2a cells [51, 52]}. A similar change in neuronal membrane properties was reported for synaptosomal membranes . These data argue that the early accumulation of rPrPSc in neuronal plasma membranes should not be ignored. Finally, the importance of lipid raft domains must be emphasized because γ-secretase , Notch-1, and the glycolipid-anchored proteins (PrPC, and PrPSc), all are concentrated within rafts. This most likely explains why quinacrine and the γ-secretase inhibitor work synergistically to decrease rPrPSc and to prevent dendritic degeneration. The data suggest that dendritic degeneration is mediated by the γ-secretase complex. Furthermore, the response of PrPSc to GSI + Qa raises the possibility that the conversion of PrPC to PrPSc is also mediated, at least in part, by the γ-secretase system.
We thank Bernadette DeArmond, MD, MPH, for editing the manuscript. This work was funded by National Institutes of Health Grants AG10770, AG02132, AG021601 and NS041997, and by the Stephen and Patricia Schott Family Fund.
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