A prion disease initiation model

based on a credible candidate for

protein X

enables detection of human

exposure to BSE, in serum.

Bergmann J, Bergmann R, Janetzky B, Preddie E

Altegen, Inc.

PrP gene

induced expression

constitutiveexpression

PrPCprionin

multi-factorial events (unknown)

prin gene

disease initiation

Altegen, Inc.

• Prionin genes are present in all mammals investigated so far

• Prionins have unique species-specific antigenic epitopes

• Pure, synthetic bovine prionin converts human native PrP in a cross-species manner, and recombinant bovine PrP, to conformers with a 27-29 kDa PK- resistant core under physiological conditions within minutes of contact, in a test tube

• We suggest that prionins are protein-X, the illusive converting factor in TSE, and add that prionins play a role in TSE initiation

• The model which follows shows how prionins provide means for the detection of human exposure to TSE

humans deer rabbitcattle moose hamstersheep elk horsemouse (atypical)

human PK-resistant PrP PrP 5 15 25 min

human PrP rec. PrP 30‘ 90‘ 30‘

29 k -

29 k -

Altegen, Inc.

PrP gene

induced expression

constitutiveexpression

PrPCprionin

prin gene

disease initiation

immunemodulation

Altegen, Inc.

Detection by a specificantibody-trap ELISA

1 prionin gene is induced

2 the expressed prionin elicits an immune response, inhibiting disease symptoms

3 the immune response declines with time in some cases

4 released from immune control, prionins interact with PrP and convert it to PrPSc

5 prionins are chaperoned to the brain complexed to PrPSc; in the brain, the complex dissociates at the neuronal membrane

6 converted PrP (PrPSc) is deposited extra-neuronally

7 prionins enter the neuronal membranes and initiate neurodegeneration

Altegen, Inc.

immunemodulation

humanprionin (prinH)

constitutiveexpression

escape

PrPSc

depos.

TSE initiation model for vCJD

PrPC

induced expression

con-

version

PrP geneprin gene

cellularmembranes

neuro-degener.

4

67

1

5

multi-factorial events

2

toxic inter-mediate

3

disease initiation

Altegen, Inc.

bovineprionin (prinB)

external source

immunemodulation

humanprionin (prinH)

constitutiveexpression

escape

PrPSc

depos.

toxic inter-mediates

TSE initiation model for vCJD

PrPC

induced expression

con-

version

PrP geneprin gene

cellularmembranes

neuro-degener.

3 4

67

1

5

multi-factorial events

2

immunemodulation

escape

2a

3

1a

external source

disease initiation

1 prionin gene is induced

2 the expressed prionin elicits an immune response, inhibiting disease symptoms

3 the immune response declines with time in some cases

4 released from immune control, prionins interact with PrP and convert it to PrPSc

5 prionins are chaperoned to the brain complexed to PrPSc; in the brain, the complex dissociates at the neuronal membrane

6 converted PrP (PrPSc) is deposited extra-neuronally

7 prionins enter the neuronal membranes and initiate neurodegeneration

OD495nm

0.5 –

-

0.4 –

-

0.3 –

-

0.2 –

-

0.1 –

-

0.0 –anti-prinB anti-prinH

5 m

onth

s

7 m

onth

s

20

mon

ths

anti-prionin antibodies in a suspected vCJD patient

Altegen, Inc.

5 m

onth

s

7 m

onth

s

20

mon

ths

Anti-bovine prionin antibody in blood bank samples

number ofsamples

number of positives

3000 -

2000 -

1000 -

0 -

- 20

- 10

- 0

2883 -

571 -

- 0

- 4

2003country 1

1996-8country 2

Altegen, Inc.

Altegen, Inc.

Conclusion

• Prionins are TSE-related proteins

• Transmitted (contaminating) prionins elicit an immune response

• Anti-prionin ELISAs can detect this immune response in blood

• Endogenous prionins are related to TSE-initiation

• They elicit an auto-immune response

• Anti-prionin ELISAs can detect the auto-immune response in blood

• We suggest that the anti-prionin ELISA should be used routinely to test blood donations for exposure to TSE

Thank you for your attention

Altegen, Inc.