prions

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(my daughter found this because i could not explain to her what a prion is

..... so i am sharing...... B MN)

Introduction

Transmissible spongiform enchephalalopathies such as Creuzfeldt-Jakob Disease

in man and Bovine Spongiform Encephalopathy in cattle are attracting much

media interest due to the possible link between BSE and a novel form of CJD.

These diseases are thought to be caused by strange agents called prions.

These are abnormal forms of a normal protein found in the membranes of our

cells, especially those in the brain and spinal cord, and in some lymphatic

tissues.

Work in our group is looking at how infection with scrapie leads to abnormal

brain function. We have already found that brain function changes before the

classical spongy histology develops. This may correspond to some cases in man

that seem to be prion disease, but which lack the classical histopathology.

We now have evidence that, late in the progress of the disease, the

properties of individual neurons changes radically.

 

Electrophysiological changes in transgenic mice - Jefferys, Empson,

Whittington & Prusiner 1994

 

Transgenic mice which overexpress the normal prion protein gene from the

Syrian hamster become susceptible to the Sc237 strain of scrapie (, M.,

et al, Cell, 59 (1989) 847-857). This strain of scrapie was first isolated

from Cheviot sheep and subsequently adapted to Syrian hamsters. The

incubation time is relatively fast, about 60-65 days. The first

electophysiological changes preceded the onset of neurological symptoms and

spongiform histopathology both of which became apparent at about 57 days.

Recordings from neocortical (A-C) and hippocampal (D) slices prepared from

control (top row) and scrapie infected Tg(SHaPrP+/+)81 mice

Grossly abnormal responses to electrical stimulation of inputs to the

neocortex appeared by 30 days after intracerebral inoculation with Sc237

scrapie. The extracellular (A) and intracellular ( records from

scrapie-infected mice look like severe epileptic discharges, with intense

excitation and excessive synchronisation of the cortical neuronal population.

A little later in the course of the disease, the properties of individual

neurons became very abnormal, with very broad action potentials in response

to injecting depolarising current into the neurons. © Illustrates an

extreme case from a neocortical neuron (these traces are superimposed in the

lowest part of panel D). The upper part of D shows recordings from one

control and one scrapie-infected CA1 hippocampal pyramidal cell. C control,

Sc = scrapie, and N = scrapie with added nitrendipine; the reduction of the

duration of the abnormal action potential suggests that caclium channels play

a role, while the lack of a fast afterhyperpolarisation might suggest a

malfunction of potassium channels

Jefferys, J.G.R., Empson, R.M., Whittington, M.A. and Prusiner, S.B., Scrapie

infection of transgenic mice leads to network and intrinsic dysfunction of

cortical and hippocampal neurons, Neurobiol.Dis., 1 (1994) 25-30.

 

Electrophysiological changes in hamsters - Barrow, Holmgren, Tapper &

Jefferys, submitted

Syrian hamsters are the adaptive host for Sc237 scrapie. They succumb to the

disease about 80 days after intracerebral inoculation. In spite of the rapid

progression of the disease, spongiform histopathology is very limited

(Hecker, R. et al Genes Dev., 6 (1992) 1213-1228). In our

elecrtrophysiological studies of brain slices from these animals we found

significant changes in the properties of individual neurons in the neocortex

and the CA1 region of the hippocampus. The main changes were a reduction of

the slow afterhyperpolarisation following repeated stimulation, and a

weakening of the potentiation of the depolarising afterpotential seen after

each action potential.

Slow afterhyperpolarisation is smaller in scrapie-infected hamsters

The large signal to the left of these superimposed traces is due to the

action potentials used to trigger the medium and slow afterhyperpolarisations

(AHPs), which are the slow negative-going waves occupying the right-hand two

thirds. The AHP is almost absent from the infected hamster, taken 71 days

after inoculation. For the analysis we determine the relationship of the

amplitude of the AHP as a function of the number of action potentials used to

evoke the event.

Amplitudes of medium and slow (or late) AHPs from the whole study, as a

function of time.

The medium AHPs (mAHP, left side) and late AHPs (lAHP, right side) for

pyramidal cells from CA1 in the hippocampus (A, top) and neocortex (B,

bottom). Asterisks indicate significant differences from control (multiple

comparisons, following ANOVA; P<0.05)

Potentiation of depolarising afterpotentials is weakened.

The depolarising afterpotential is the positive tail to each action

potential. Note how, in the control case, it grows with successive action

potentials. This potentiation is much smaller in a typical late scrapie case;

in many cases potentiation is absent.

 

Overall the study on the natural Syrian hamster host for this kind of scrapie

shows that the physiology of individual neurons is markedly disrupted.

Histopathology was virtually undetectable, even when the hamsters were in the

terminal stages of the disease, and would die within a few days. We did find

modest changes in the branching patterns of the dendrites of pyramidal cells

towards the end of the course of the disease - an increase in the branching

of the basal dendrites for both neocortical and hippocampal neurons.

The physiological changes were much less dramatic than for the Tg81 mice,

presumably because of the mulitple copies of the normal hamster prion gene

expressed in these mice. Nevertheless the marked reduction in AHPs ofund in

the hamsters would contribute to the hypersynchronous EEGs of the kind

reported for scrapie in sheep and rats and for CJD in humans. The fact that

both DAP potentiation and AHP amplitudes are affected might suggest a primary

deficit in the control of intracellular calcium. However, this must be

selective for channels that are specifically responsible for these processes,

because other calcium-dependent events are not affected by the disease.

The next stage is to find out whether similar changes occur in CJD and new

varient CJD......

Barrow, P.A. and Jefferys, J.G.R., Reduced afterhyperpolarisations in

principal cells of the hippocampus and neocortex in a hamster model of

scrapie, Eur.J.Neurosci., 10, Suppl. 10 (1998) 314