2007 CJD Presentation - Graham Steel

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Information about 2007 CJD Presentation - Graham Steel
Health & Medicine

Published on September 22, 2008

Author: steelgraham

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most recent version of my CJD related presentation

2007 Presentation CJD Support Organisations Transmissible Spongiform Encephalopathy (TSE’s) The Nature of TSE Disease Transmission Overall Prognosis in PrP d terms

CJD Support Organisations

Transmissible Spongiform Encephalopathy (TSE’s)

The Nature of TSE Disease Transmission

Overall Prognosis in PrP d terms

1992 CJD Support Group Network Inc. - Australia 1993 CJD Foundation – United States 1994 Association of Victims of Growth Hormone - France 1994 CJD Support Network – United Kingdom 1995/6 Human BSE Foundation – United Kingdom 1997 CJD Voice – United States 1998 CJD Watch – United States 2001 CJD Aware – United States 2002 CJD Support Network – Japan 2003 FFI Families Association 2005 CJD Alliance 2006 CJD International Support Alliance CJD Support Groups - Timeline

1992 CJD Support Group Network Inc. - Australia

1993 CJD Foundation – United States

1994 Association of Victims of Growth Hormone - France

1994 CJD Support Network – United Kingdom

1995/6 Human BSE Foundation – United Kingdom

1997 CJD Voice – United States

1998 CJD Watch – United States

2001 CJD Aware – United States

2002 CJD Support Network – Japan

2003 FFI Families Association

2005 CJD Alliance

2006 CJD International Support Alliance

For a variety of reasons, across the World, several Support Groups/Organisations and Individuals have emerged over the last decade or so Many challenges exist in an area with a number of uncertainties in this rare group of invariably fatal neurodegenerative diseases Ignorance of these unusual properties led to inadvertent outbreaks of iatrogenic (surgically-induced, accidentally transmitted) CJD through fledgling experiments on humans from the 1950s with pituitary infertility drugs (hPH), human growth hormone (hGH) injections in children, grafts of Dura mater in brain and spinal operations, Corneal transplantation and the re-use of surgical instruments after procedures on people with CJD. The Formation, Growth and Roles of CJD Support Groups

For a variety of reasons, across the World, several Support Groups/Organisations and Individuals have emerged over the last decade or so

Many challenges exist in an area with a number of uncertainties in this rare group of invariably fatal neurodegenerative diseases

Ignorance of these unusual properties led to inadvertent outbreaks of iatrogenic (surgically-induced, accidentally transmitted) CJD through fledgling experiments on humans from the 1950s with pituitary infertility drugs (hPH), human growth hormone (hGH) injections in children, grafts of Dura mater in brain and spinal operations, Corneal transplantation and the re-use of surgical instruments after procedures on people with CJD.

Background The biggest TSE killer in humans is CJD, first identified in the 1920s by German neuropsychiatrists Alfons Jakob and Hans Creutzfeldt. Since then, painstaking detective work by scientists in the United States, Europe, Australia and Japan has followed the zigzag course of the disease. TSEs, or prion diseases, are not only infectious, they are also inheritable in a very small number of cases. They have no cure and no validated pre-mortem test, so absolute confirmation cannot be made until a post-mortem examination of the brain. However, developments over the last few years provide much encouragement. The most common form of the disease - Classical CJD - occurs at a rate of about one to two per million people in many countries annually, mainly (but not always) in older people. It has no known cause to date. As of Dec 2003 – vCJD has been proven to be transmitted via blood. Whatever the cause - a yet-to-be identified virus, Virino, or "prion" (a corrupted naturally occurring protein) - TSEs are among the worst diseases yet identified. The infective agent appears to bind to alcohol-based disinfectants and resists heating to phenomenal temperatures, freezing, burial underground for years, the strongest of chemicals and conventional surgical sterilisation.

Background and Current Day Issues CJD collectively was generally an “unheard of” condition until the advent of the emergence of vCJD in 1996 in the UK which “changed the landscape” of CJD Over the last few years, the level and depth of contact between a number of Support Groups has evolved, namely due to use of the Internet Many Support Groups are now linked to each other from their respective websites Sharing our experiences, knowledge, aspirations, concerns, achievements and goals should be encouraged Collaboration amongst researchers and scientists should be encouraged

Background and Current Day Issues Through the global unity that continues to grow, I firmly believe that by forming such a Global Alliance, these groups combined voice and strength for those who have lost, those current suffering from, and those sadly still to come in the future is and will always be really important. Graham Steel, 2005

 

v CJD and It's Effect on the Brain Frontal Lobe - behavioural changes, personality changes, psychosis, hallucinations and other forms of dementia Cerebellum - tremors, muscle spasms, loss of ability to walk and involuntary movements Parietal Lobe - spatial orientation, voluntary movement and touch perception Brain Stem - blood pressure, heart rate, breathing, body temperature and ability to sleep Temporal Lobe - the ability to understand speech, hear and remember Occipital Lobe - abnormal or loss of vision

Frontal Lobe - behavioural changes, personality changes, psychosis, hallucinations and other forms of dementia

Cerebellum - tremors, muscle spasms, loss of ability to walk and involuntary movements

Parietal Lobe - spatial orientation, voluntary movement and touch perception

Brain Stem - blood pressure, heart rate, breathing, body temperature and ability to sleep

Temporal Lobe - the ability to understand speech, hear and remember

Occipital Lobe - abnormal or loss of vision

FLAIR MR(I) IMAGING c CJD compared with v CJD Detection results on patient data. Left (1 and 2 ) a cCJD case with stronger hyperintensities in the head of caudate and putamen. Right (3 and 4) a vCJD case with stronger hyperintensities in the pulvinar. We present for each case an original cross-section of the FLAIR MR image with abnormal hyperintensities in the internal nuclei and next the same cross-section superimposed with the CJD detection map

Thalamus Diffusion weighted MRI findings are not included among the major diagnostic criteria, although DWI is more sensitive than EEG and can detect lesions at an early stage. Even in cases of sCJD without the classical triad, we can make a correct diagnosis more easily if we know the specific imaging finding for a specific subtype. In the case of sCJD with VV2, which does not show prominent myoclonic jerks or PSWCs (Periodic sharp wave complexes) in the EEG, the characteristic thalamic lesions demonstrated in DWI may lead to an exact diagnosis. These characteristic thalamic lesions can also be an important clue to distinguish sCJD with VV2 from vCJD, because the major differential diagnosis of vCJD is sCJD without PSWCs.

Diffusion weighted MRI findings are not included among the major diagnostic criteria, although DWI is more sensitive than EEG and can detect lesions at an early stage.

Even in cases of sCJD without the classical triad, we can make a correct diagnosis more easily if we know the specific imaging finding for a specific subtype.

In the case of sCJD with VV2, which does not show prominent myoclonic jerks or PSWCs (Periodic sharp wave complexes) in the EEG, the characteristic thalamic lesions demonstrated in DWI may lead to an exact diagnosis.

These characteristic thalamic lesions can also be an important clue to distinguish sCJD with VV2 from vCJD, because the major differential diagnosis of vCJD is sCJD without PSWCs.

Neuropathologic characteristics of brainstem lesions in Classical Creutzfeldt-Jakob disease. Iwasaki Y, Hashizume Y, Yoshida M, Kitamoto T, Sobue G. Acta Neuropathol (2005) 109: 557–566 DOI 10.1007/s00401-005-0981-0 The density of PrP deposition in the sCJD brainstem was not associated with disease duration or neuronal degeneration until the late stage. Our results show that atrophy, neuronal loss, and pyramidal tract degeneration occur in the sCJD brainstem, particularly in patients with an unusually prolonged disease course. These findings are not associated directly with PrP deposition and may reflect end-stage sCJD. No VV1, VV2, or MV2 cases were included in our study; however, we suggest that widespread and relatively stereotypic PrP deposition is a consistent pathologic feature of sCJD, at least in MM1 sCJD patients. Although accumulation of PrP in the brainstem appears to be an early pathologic event in sCJD, and may remain into the late disease stage, the brainstem remains relatively resistant to the pathologic process of sCJD. COMMENT- Apart from specific blood tests (genotype) for inherited forms of Prion disease, reliable tests for TSEs before the onset of clinical symptoms is an ultimate goal.

The density of PrP deposition in the sCJD brainstem was not associated with disease duration or neuronal degeneration until the late stage. Our results show that atrophy, neuronal loss, and pyramidal tract degeneration occur in the sCJD brainstem, particularly in patients with an unusually prolonged disease course.

These findings are not associated directly with PrP deposition and may reflect end-stage sCJD.

No VV1, VV2, or MV2 cases were included in our study; however, we suggest that widespread and relatively stereotypic PrP deposition is a consistent pathologic feature of sCJD, at least in MM1 sCJD patients.

Although accumulation of PrP in the brainstem appears to be an early pathologic event in sCJD, and may remain into the late disease stage, the brainstem remains relatively resistant to the pathologic process of sCJD.

COMMENT- Apart from specific blood tests (genotype) for inherited forms of Prion disease, reliable tests for TSEs before the onset of clinical symptoms is an ultimate goal.

Peripheral Nerve's (PN’s) and Dorsal Root Ganglion (DRG) Conditioned medium enhances axonal outgrowth from PN-DRGs. PN-DRGs after culture in collagen gels for 3 d, labeled with an antibody to PGP 9.5 (visualized with HRP conjugated avidin) taken using dark-ground illumination to make it easier to see fine axons at low magnification. In a control preparation ( A ) cultured in RPMI medium, only a few axons have grown out of the cut end of the peripheral nerve, whereas extensive axonal outgrowth has occurred from a preparation cultured inmedium conditioned by lesioned sciatic nerve segments ( B ). Scale bar, 200_m. DOI:10.1523/JNEUROSCI.5089-06.2007 Copyright©2007 Society for Neuroscience 0270-6474/07/271190-10$15.00/0

CNS -> Brain New Scientist © 2006

New Scientist © 2006

Neuropathologic characteristics of brainstem lesions in Classical Creutzfeldt-Jakob disease.

Neuropathologic characteristics of brainstem lesions in Classical Creutzfeldt-Jakob disease. This paper states that that the Dorsal Vagal Nucleus (DVN) was positive for PrP d in 27 out of 33 victims. This is much the same as cattle with BSE, sheep with Scrapie and deer/cervids with CWD. This strongly suggests that heart rate variability (HRV) may be a useful test for cCJD since HRV indicates activity in the dorsal vagal nucleus (DVN) (it is comprised of the cell bodies from the same neurones that make up the vagus nerve). Iwasaki Y, Hashizume Y, Yoshida M, Kitamoto T, Sobue G. Acta Neuropathol (2005) 109: 557–566 DOI 10.1007/s00401-005-0981-0

This paper states that that the Dorsal Vagal Nucleus (DVN) was positive for

PrP d in 27 out of 33 victims. This is much the same as cattle with BSE, sheep

with Scrapie and deer/cervids with CWD.

This strongly suggests that heart rate variability (HRV) may be a useful test

for cCJD since HRV indicates activity in the dorsal vagal nucleus (DVN)

(it is comprised of the cell bodies from the same neurones that make up the vagus nerve).

Neuropathologic characteristics of brainstem lesions in Classical Creutzfeldt-Jakob disease. How did PrP d get there? The possibilities are: The “spontaneous event” (“n” of 33) that gave these victims of cCJD also lead to the Prion spreading to the dorsal vagal by an unknown route in 27 cases Blood, in which case sCJD is carried in the blood. If so, why didn’t all the patients get a stained dorsal vagal nucleus? 3. Cerebrospinal fluid (CSF), in which case why didn’t all the patients get a stained dorsal vagal nucleus and everywhere else since the whole brain is bathed in CSF? Vagal infection from food ingested in the gut (as in BSE and CWD). This would suggest that 27 got sCJD from food/orally, and the remaining 6 from other causes

How did PrP d get there? The possibilities are:

The “spontaneous event” (“n” of 33) that gave these victims of cCJD also lead to the

Prion spreading to the dorsal vagal by an unknown route in 27 cases

Blood, in which case sCJD is carried in the blood. If so, why didn’t all the

patients get a stained dorsal vagal nucleus?

3. Cerebrospinal fluid (CSF), in which case why didn’t all the patients get a

stained dorsal vagal nucleus and everywhere else since the whole brain is

bathed in CSF?

Vagal infection from food ingested in the gut (as in BSE and CWD). This

would suggest that 27 got sCJD from food/orally, and the remaining 6 from other causes

 

ORAL SCRAPIE SPREADS ALONG SPLANCHNIC AND VAGUS NERVES PATRICIA A. MCBRIDE,1* WALTER J. SCHULZ-SCHAEFFER,2† MAURA DONALDSON,1 MOIRA BRUCE,1 H. DIRINGER,3 HANS A. KRETZSCHMAR,2 AND MICHAEL BEEKES3

Blood Transfusion Sheep PrP d in brainstem after blood transfusion

Neuropathologic characteristics of brainstem lesions in Classical Creutzfeldt-Jakob disease. How did PrPd get there? The possibilities are: If 4 is correct, this is very new and alarming. Prof Collinge et al has suggested that inoculating mice with BSE sometimes leads to cCJD as well as vCJD like conditions Bearing in mind the increasing incidence of CJD world-wide, perhaps this should be investigated further? Collinge and colleagues described transmission of BSE to humanised transgenic mice and the occurrence of a distinct type of PrPSc in VV mice inoculated with vCJD. These differing findings are probably due to the fact that the mice used in the previous studies, which were generated by introducing multiple copies of the human gene into a PrP knockout mouse, expressed twice to fourfold the physiological concentrations of PrP found in human brain. However, the major finding of both Collinge’s group and the current study by Bishop and colleagues is the existence of subclinical infections in all codon-129 genotypes.

How did PrPd get there? The possibilities are:

If 4 is correct, this is very new and alarming. Prof Collinge et al has suggested that

inoculating mice with BSE sometimes leads to cCJD as well as vCJD like

conditions

Bearing in mind the increasing incidence of CJD world-wide, perhaps this

should be investigated further?

Collinge and colleagues described transmission of BSE to humanised transgenic mice and the occurrence of a distinct type of PrPSc in VV mice inoculated with vCJD. These differing findings are probably due to the fact that the mice used in the previous studies, which were generated by introducing multiple copies of the human gene into a PrP knockout mouse, expressed twice to fourfold the physiological concentrations of PrP found in human brain. However, the major finding of both Collinge’s group and the current study by Bishop and colleagues is the existence of subclinical infections in all codon-129 genotypes.

Predicting susceptibility and incubation time human-to-human transmission of vCJD Interpretation Transmission of BSE to human beings is probably restricted by the presence of a significant species barrier. However, there seems to be a substantially reduced barrier for human-to-human transmission of vCJD. Moreover, all individuals, irrespective of codon-129 genotype, could be susceptible to secondary transmission of vCJD through routes such as blood transfusion. A lengthy preclinical disease is predicted by these models, which may represent a risk for further disease transmission and thus a significant public-health issue. M T Bishop, P Hart, L Aitchison, H N Baybutt, C Plinston, V Thomson, N L Tuzi, M W Head, J W Ironside, R G Will, J C Manson http://neurology.thelancet.com Published online March 27, 2006 DOI: 10.1016/S1474-4422(06)70413-6

Interpretation

Transmission of BSE to human beings is probably restricted by the presence of a significant species barrier. However, there seems to be a substantially reduced barrier for human-to-human transmission of vCJD. Moreover, all individuals, irrespective of codon-129 genotype, could be susceptible to secondary transmission of vCJD through routes such as blood transfusion. A lengthy preclinical disease is predicted by these models, which may represent a risk for further disease transmission and thus a significant public-health issue.

http://neurology.thelancet.com Published online March 27, 2006 DOI: 10.1016/S1474-4422(06)70413-6

Prions and their lethal journey to the brain Abstract | Prion diseases are neurodegenerative conditions that cause extensive damage to nerve cells within the brain and can be fatal. Some prion disease agents accumulate first in lymphoid tissues, as they make their journey from the site of infection, such as the gut, to the brain. Studies in mouse models have shown that this accumulation is obligatory for the efficient delivery of prions to the brain. Indeed, if the accumulation of prions in lymphoid tissues is blocked, disease susceptibility is reduced. Therefore, the identification of the cells and molecules that are involved in the delivery of prions to the brain might identify targets for therapeutic intervention. This review describes the current understanding of the mechanisms involved in the delivery of prions to the brain. Neil A. Mabbott* and G. Gordon MacPherson‡ FURTHER INFORMATION Neil Mabbott’s homepage: http://www.iah.bbsrc.ac.uk/ primary_index/current_research/groups/TSE_Division/TSEImmPathGp. htm Gordon MacPherson’s homepage: http://users.path.ox.ac. uk/~ggm Scottish TSE Network: http://www.stn.ed.ac.uk UK Creutzfeldt-Jakob disease Surveillance Unit: http://www.cjd.ed.ac.uk/index.htm The inquiry into BSE and vCJD in the United Kingdom: http://www.bseinquiry.gov.uk Chronic Wasting Disease alliance: http://www.cwd-info.org ImmunoTSE: http://immunotse.vitamib.com NeuroPrion: a network of excellence on prion diseases: http://www.neuroprion.org/home.html

Abstract | Prion diseases are neurodegenerative conditions that cause extensive damage to nerve cells within the brain and can be fatal. Some prion disease agents accumulate first in lymphoid tissues, as they make their journey from the site of infection, such as the gut, to the brain. Studies in mouse models have shown that this accumulation is obligatory for the

efficient delivery of prions to the brain. Indeed, if the accumulation of prions in lymphoid tissues is blocked, disease susceptibility is reduced. Therefore, the identification of the cells and molecules that are involved in the delivery of prions to the brain might identify targets for therapeutic intervention. This review describes the current understanding of the mechanisms involved in the delivery of prions to the brain.

Neil A. Mabbott* and G. Gordon MacPherson‡

Figure 4 | Initial pathways of transmissible spongiform encephalopathy (TSE) agent neuroinvasion from the intestine. Analysis of the progression of disease-specific prion protein (PrP) accumulation within the nervous system of experimentally inoculated rodents indicates that the scrapie agent spreads from the intestine to the central nervous system (CNS) through two distinct neuroanotomical pathways95. In each case, the initial spread occurs in a retrograde direction along efferent (motor) pathways in a stepwise manner between synaptically linked sets of nerves. One route to the CNS occurs along sympathetic fibres of the splanchnic nerve to the intermediolateral cell column (IML) of the mid-thoracic spinal cord. Subsequently, the agent spreads to the brain in a caudal-to-cranial direction along the spinal cord. Neuroinvasion from the intestine can also occur independently of the spinal cord. In this case, the agent spreads along parasympathetic fibres of the vagus nerve to the dorsal motor nucleus of the vagus nerve (DMNV) within the medulla oblongata of the brain. GALT, gut-associated lymphoid tissues. © 2006 Nature Publishing Group

The Nature of TSE Disease Transmission Although critical to the understanding of TSE diseases, the most fundamental aspect of such is still controversial: i.e. What is the nature of the agent that transmits these debilitating diseases? The scientific community is divided namely between two possibilities * : * Other theories also exist (Prof Laura Manuelidis, Prof Alan Ebringer, Mark Purdey etc)

PrP From microbes to prions the final proof of the prion hypothesis? Zou WQ, Gambetti P. Division of Neuropathology, Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH 44106, USA. Much like the "microbe hypothesis" put forth over 150 years ago, the "prion hypothesis" can be definitely proven only if a prion disease is engendered in a natural host from an infectious prion produced in vitro. In this issue of Cell, they come very close to accomplishing this goal by producing a prion disease in a natural host from a prion entirely generated in vitro using a PCR-like amplification system.

From microbes to prions the final proof of the prion hypothesis? Zou WQ, Gambetti P. Division of Neuropathology, Department of Pathology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH 44106, USA. Much like the "microbe hypothesis" put forth over 150 years ago, the "prion hypothesis" can be definitely proven only if a prion disease is engendered in a natural host from an infectious prion produced in vitro. In this issue of Cell, they come very close to accomplishing this goal by producing a prion disease in a natural host from a prion entirely generated in vitro using a PCR-like amplification system.

A letter written by Dr. A.G.Dickinson, a world expert on Scrapie, to the Chairman of the Select Committee on Agriculture in January 2001 The misleading word that has been most popular with the media in recent years to describe BSE being transferred to another species is that it "jumped". I am certain that a more accurate term is that it was "pushed". In order to "push" one of these types of agents across to another species, the greater the amount of infective agent involved, the more likely it is to achieve infection of the other species. My assessment of the current situation with the transfer of BSE to humans, is that the whole picture could be explained solely in terms of the enormous scale of the BSE epidemic having massively exposed people to the otherwise very small risk of being infected.

The misleading word that has been most popular with the media in recent years to describe BSE being transferred to another species is that it "jumped". I am certain that a more accurate term is that it was "pushed".

In order to "push" one of these types of agents across to another species, the greater the amount of infective agent involved, the more likely it is to achieve infection of the other species.

My assessment of the current situation with the transfer of BSE to humans, is that the whole picture could be explained solely in terms of the enormous scale of the BSE epidemic having massively exposed people to the otherwise very small risk of being infected.

The simplified layout shown below, using A or B for the two variants of Sinc (Scrapie Inclusive), illustrates these points but does not refer to actual strains: dose and route of infection are the same for all the examples. Different scrapie strains were distinguishable because they differed in their relative incubation periods between the 3 Sinc genotypes of the inbred mice. scrapie strain 1 AA AB BB strain 2 AA AB BB strain 3 AA BB AB strain 4 AA AB BB strain 5 AA BB |-> strain 6 BB AA AB strain 7 BB AA AB strain 8 BB AA AB |<---/ /-------------------------------------- LIFESPAN ----------------------------------------------  | S inc = Scrapie Inclusive

scrapie

strain 1 AA AB BB

strain 2 AA AB BB

strain 3 AA BB AB

strain 4 AA AB BB

strain 5 AA BB |->

strain 6 BB AA AB

strain 7 BB AA AB

strain 8 BB AA AB

|<---/ /-------------------------------------- LIFESPAN ----------------------------------------------  |

Conclusion Obviously, one allele could not be described as producing short incubation, and the other one long incubation because this was reversed for some strains of agent. All except two types of pattern have been found. The two relevant variables - dose and route - can be varied so that clinical disease for some genotypes tends to be displaced beyond the lifespan by increasing the incubation period, namely [1] by lower doses, or [2] by routes with lower efficiencies than intracerebral injection. It is reasonable to expect that this general diagram and comments apply to all TSE’s, in all species. The details for any untested combinations are unpredictable in our present state of knowledge. These basic findings posed the question of how the Sinc gene could be operating at the molecular level. They prompted the proposal in 1971 that the gene was producing a protein (now called PrP) which grouped to form the replication sites for TSE agents.

Obviously, one allele could not be described as producing short incubation, and the other one long incubation because this was reversed for some strains of agent. All except two types of pattern have been found. The two relevant variables - dose and route - can be varied so that clinical disease for some genotypes tends to be displaced beyond the lifespan by increasing the incubation period, namely

[1] by lower doses, or

[2] by routes with lower efficiencies than intracerebral injection.

It is reasonable to expect that this general diagram and comments apply to all

TSE’s, in all species.

The details for any untested combinations are unpredictable in our present state of knowledge.

These basic findings posed the question of how the Sinc gene could be operating at the

molecular level. They prompted the proposal in 1971 that the gene was producing a

protein (now called PrP) which grouped to form the replication sites for TSE agents.

Embargoed until the publication of the BSE Inquiry’s Report The BSE Inquiry and the vCJD Families Press Briefing September 2000 Irwin Mitchell Solicitors “ Insufficient research was undertaken into means of ameliorating the progress of vCJD. In particular, the Families are concerned that the work on Dextran Sulphate 500 and Pentosan Polysulphate undertaken at the ARC Neuropathogenesis Unit [NPU] during the 1970's was not immediately revisited once vCJD had been identified in 1996”.

Embargoed until the publication of the BSE Inquiry’s Report

The BSE Inquiry and the vCJD Families

Press Briefing September 2000 Irwin Mitchell Solicitors

“ Insufficient research was undertaken into means of ameliorating the progress of vCJD. In particular, the Families are concerned that the work on Dextran Sulphate 500 and Pentosan Polysulphate undertaken at the ARC Neuropathogenesis Unit [NPU] during the 1970's was not immediately revisited once vCJD had been identified in 1996”.

Polyanions and the Proteome From the Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047-3729 “Polyanions and the Proteome” (2004) Molecular & Cellular Proteomics 3.8 doi:10.1074/mcp.R400008-MCP200

Polyanions and the Proteome “Crowded House” From the Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047-3729 “Polyanions and the Proteome” (2004) Molecular & Cellular Proteomics 3.8 doi:10.1074/mcp.R400008-MCP200 The very crowded environment of the cell. Actin ( red ), macromolecules, primarily ribosomes ( green ), and membranes ( blue ) are represented. Reprinted with permission from Medalia, O., Weber, I., Frangakis, A. S., Nicastro, D., Gerisch, G. and Baumeister, W. (2002) Macromolecular architecture in eukaryotic cells visualized by cryoelectron topography. Science 298, 1209–1213. Copyright 2002, AAAS.

Prions and their partners in crime Prions, the infectious agents of transmissible spongiform encephalopathies (TSEs), have defied full characterization for decades. The dogma has been that prions lack nucleic acids and are composed of a pathological, self-inducing form of the host’s prion protein (PrP). Recent progress in propagating TSE infectivity in cell-free systems has effectively ruled out the involvement of foreign nucleic acids. However, host-derived nucleic acids or other non-PrP molecules seem to be crucial. Interactions between TSE associated PrP and its normal counterpart are also pathologically important, so the physiological functions of normal PrP and how they might be corrupted by TSE infections have been the subject of recent research. From: Caughey B & Baron GS (2006) “Prions and their partners in crime” Nature 443 doi:10.1038/nature05294

Prions, the infectious agents of transmissible spongiform encephalopathies (TSEs), have defied full

characterization for decades. The dogma has been that prions lack nucleic acids and are composed of

a pathological, self-inducing form of the host’s prion protein (PrP). Recent progress in propagating TSE

infectivity in cell-free systems has effectively ruled out the involvement of foreign nucleic acids. However,

host-derived nucleic acids or other non-PrP molecules seem to be crucial. Interactions between TSE associated

PrP and its normal counterpart are also pathologically important, so the physiological functions of

normal PrP and how they might be corrupted by TSE infections have been the subject of recent research.

Prions and their partners in crime From: Caughey B & Baron GS (2006) “Prions and their partners in crime” Nature 443 doi:10.1038/nature05294 PrPc

Prions and their partners in crime From: Caughey B & Baron GS (2006) “Prions and their partners in crime” Nature 443 doi:10.1038/nature05294

Prions and their partners in crime From: Caughey B & Baron GS (2006) “Prions and their partners in crime” Nature 443 doi:10.1038/nature05294 Transport of PrP d within neurones

From extracellular matrix into the “Crowded House” The Journal of Infectious Diseases 2006; 194:702–9 0022-1899/2006/19405-0024 Sabine Gauczynski, Daphne Nikles, Susanne El-Gogo, Dulce Papy-Garcia, Clemence Rey, Susanne Alban, Denis Barritault, Corinne Ida Lasmezas, and Stefan Weiss

GAG = G lycos a mino g lycan’s Polyanionic therapeutics directed toward the protein-solubility diseases are in development. The Canadian-based company Neurochem (Laral, Quebec, Canada) has two “GAG mimetic” drug candidates [Fibrillex™ (phase II/III) and Azhemed™ (phase II completed, extended phase II underway) in advanced clinical trials. Fibrillex™ is directed toward AA amyloidosis , a fatal disorder with characteristic amyloid deposits in the liver, spleen, and kidney. Similar to Alzheimer’s disease , GAGs have also been isolated in the amyloid deposits of AA amyloidsis patients. The rationale for using GAG mimetics in the treatment of both conditions is that these small GAG analogues can competitively inhibit the binding of endogenous GAGs to AA or A proteins, thereby preventing fibrillation. The company’s drug candidate for the treatment of Alzheimer’s disease similarly is designed to prevent the formation of fibrils by binding to soluble A and to inhibit the deposition of brain A fibrils. The success of these approaches in humans remains to be determined, but studies in animal models are promising. From the Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047-3729 “Polyanions and the Proteome” (2004) Molecular & Cellular Proteomics 3.8 doi:10.1074/mcp.R400008-MCP200

Polyanionic therapeutics directed toward the protein-solubility

diseases are in development. The

Canadian-based company Neurochem (Laral, Quebec,

Canada) has two “GAG mimetic” drug candidates [Fibrillex™

(phase II/III) and Azhemed™ (phase II completed, extended

phase II underway) in advanced clinical trials. Fibrillex™ is

directed toward AA amyloidosis , a fatal disorder with characteristic

amyloid deposits in the liver, spleen, and kidney. Similar

to Alzheimer’s disease , GAGs have also been isolated in

the amyloid deposits of AA amyloidsis patients. The

rationale for using GAG mimetics in the treatment of both

conditions is that these small GAG analogues can competitively

inhibit the binding of endogenous GAGs to AA or A

proteins, thereby preventing fibrillation. The company’s

drug candidate for the treatment of Alzheimer’s disease

similarly is designed to prevent the formation of fibrils by

binding to soluble A and to inhibit the deposition of brain

A fibrils. The success of these approaches in humans

remains to be determined, but studies in animal models are

promising.

Polyanions It is in terms of proteomics that the global role of polyanions both within and without cells might have its greatest immediate consequences. What at first appears to be a series of unrelated phenomena whose only common features are the involvement of polyanionic substances, may actually reflect a broad underlying role for highly negatively charged macromolecules in diverse cellular functions and environments. The elucidation of these roles will require that polyanions be taken into account as they relate to the spatial, structural, and temporal behavior of the proteome. Tools now exist to begin to ask to what extent protein/polyanion interactions are present in cells and to probe their biological roles. From the Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66047-3729 “Polyanions and the Proteome” (2004) Molecular & Cellular Proteomics 3.8 doi:10.1074/mcp.R400008-MCP200 D , microtubule. Reprinted with permission from Baker, N. A., Sept, D., Joseph, S., Holst, M. J., and McCammon, J. A. (2001) Electrostatics of nanosystems: Applications to microtubules and the ribosome. Proc. Natl. Acad. Sci. U. S. A. 98, 10037–10041. Copyright 2001, National Academy of Sciences, U.S.A. E , 50S ribosome. Reprinted with permission from Baker, N. A., Sept, D., Joseph, S., Holst, M. J., and McCammon, J. A. (2001) Electrostatics of nanosystems: Applications to microtubules and the ribosome. Proc. Natl. Acad. Sci. U. S. A. 98, 10037–10041. Copyright 2001, National Academy of Sciences, U.S.A.

Heparan sulfate proteoglycan involvement in other amyloidoses and in prion diseases Heparan sulfate proteoglycans in amyloidoses: GAGs have consistently been found in all kinds of amyloid (e.g. AA or AL amyloidosis), regardless the type of amyloidogenic protein deposited Heparan sulfate proteoglycans in prion diseases: Immunohistochemical surveys revealed that protease-resistant prion protein (PrPres) plaques contain HSPGs as a common constituent. Polysulfated compounds inhibit deposition of PrP in scrapie-infected neuroblastoma cells, suggesting that these inhibitors were capable of blocking the interaction between PrP and endogenous HS/HSPG Jack van Horssen, MSc Dept. of Pathology University Medical Center Nijmegen The Netherlands

Heparan sulfate proteoglycans in amyloidoses:

GAGs have consistently been found in all kinds of amyloid (e.g. AA or AL amyloidosis), regardless the type of amyloidogenic protein deposited

Heparan sulfate proteoglycans in prion diseases:

Immunohistochemical surveys revealed that protease-resistant prion protein (PrPres) plaques contain HSPGs as a common constituent. Polysulfated compounds inhibit deposition of PrP in scrapie-infected neuroblastoma cells, suggesting that these inhibitors were capable of blocking the interaction between PrP and endogenous HS/HSPG

Heparan sulfate proteoglycan involvement in other amyloidoses and in prion diseases Heparan sulfate proteoglycans in  -synucleinopathies and tauopathies GAGs, in particular heparan sulfate, have the ability to induce the formation of  -synuclein fibrils in vitro. We were unable to confirm an association of HSPGs/HS with Lewy bodies and Lewy neurites (unpublished data), HSPGs and HS are present in a variable fraction of tangles associated with progressive supranuclear palsy, Pick’s disease and other tauopathies Jack van Horssen, MSc Dept. of Pathology University Medical Center Nijmegen The Netherlands

Heparan sulfate proteoglycans in  -synucleinopathies and tauopathies

GAGs, in particular heparan sulfate, have the ability to induce the formation of  -synuclein fibrils in vitro. We were unable to confirm an association of HSPGs/HS with Lewy bodies and Lewy neurites (unpublished data),

HSPGs and HS are present in a variable fraction of tangles associated with progressive supranuclear palsy, Pick’s disease and other tauopathies

Therapy approaches Both in vitro and in vivo studies demonstrated a protective activity of small polysulfated compounds against A  -induced effects Several underlying mechanisms can be responsible for the protective actions of these sulfated GAG mimetics They may: inhibit the binding of heparan sulfate to A  inhibit the formation of  -pleated sheets and block the adherence of A  to the cell surface.

Both in vitro and in vivo studies demonstrated a protective activity of

small polysulfated compounds against A  -induced effects

Several underlying mechanisms can be responsible for the protective

actions of these sulfated GAG mimetics

They may:

inhibit the binding of heparan sulfate to A 

inhibit the formation of  -pleated sheets and

block the adherence of A  to the cell surface.

Age of onset Illness duration (survival) Individuals in this study have had some form of Pentosan inducement (mainly i.c.) Human Prion Disease: Natural history. From Lesley Stewart et al .2006. 36m(a) 42m(a) 61m(a) 16m(d) 2 145 6-40m 14m 2 145 12-74yrs 28yrs vCJD 30m(a) 29m(d) 3 111 3-30m 16m 3 121 10-37yrs 26yrs iCJD (HGH) 52m(d) 60m(a) 6 21 2-84m 48m 7 38 22-71yrs 44yrs GSS P102L PPS Patients. Duration of illness studies N range Median Duration of illness studies N range Median Age of onset Type

The Families of Control Cases for access to records and those who did not participate in the prospective study but agreed to data being used. . Dr Sarah Walker and Laura Belton MRC Clinic Trials Unit for statistical advice and data handling. General Practitioners and Consultants for their interest and in helping provide records and agreeing access to patients. Also: Janet Darbyshire (MRC Clinical trials Unit). Sheila Bird (MRC Biostatistics Unit Cambridge). Margaret Leitch, Richard Knight, Bob Will (CJDSU). Ian Whittle ( Dept Clinical Neurosciences Western General Hospital Edinburgh). Steve Wroe, John Collinge (National Prion Unit. National Hospital Queen Square). Christine Farquhar (Instititute of Animal Health. Neuropathogenesis Unit Edinburgh). Leah Davidson (Institute of Child Health). Alan Dickinson (Edinburgh). Chris Pomfrett (University Dept of Anaesthetics University of Manchester) Nikolai Rainov (Walton Centre for Neurology and Neurosurgery Liverpool). Graham Steel (Glasgow). Also Lester Firkins (NTSG) and Fiona Russell, Declan Mulkeen and Graham Cadwallader (MRC) for their support. The Persons and Families suffering human prion disease who allowed Prof Ian Bone into their homes to carry out this study.

The Families of Control Cases for access to records and those who did not participate in the prospective study but agreed to data being used.

.

Dr Sarah Walker and Laura Belton MRC Clinic Trials Unit for statistical advice and data handling.

General Practitioners and Consultants for their interest and in helping provide records and agreeing access to patients.

Also:

Janet Darbyshire (MRC Clinical trials Unit).

Sheila Bird (MRC Biostatistics Unit Cambridge).

Margaret Leitch, Richard Knight, Bob Will (CJDSU).

Ian Whittle ( Dept Clinical Neurosciences Western General Hospital Edinburgh).

Steve Wroe, John Collinge (National Prion Unit. National Hospital Queen Square).

Christine Farquhar (Instititute of Animal Health. Neuropathogenesis Unit Edinburgh).

Leah Davidson (Institute of Child Health).

Alan Dickinson (Edinburgh).

Chris Pomfrett (University Dept of Anaesthetics University of Manchester)

Nikolai Rainov (Walton Centre for Neurology and Neurosurgery Liverpool).

Graham Steel (Glasgow).

Also Lester Firkins (NTSG) and Fiona Russell, Declan Mulkeen and Graham Cadwallader (MRC) for their support.

Embargoed until the publication of the BSE Inquiry’s Report The BSE Inquiry and the vCJD Families Press Briefing September 2000 Irwin Mitchell Solicitors “ Insufficient research was undertaken into means of ameliorating the progress of vCJD. In particular, the Families are concerned that the work on Dextran Sulphate 500 and Pentosan Polysulphate undertaken at the ARC Neuropathogenesis Unit [NPU] during the 1970's was not immediately revisited once vCJD had been identified in 1996”.

Embargoed until the publication of the BSE Inquiry’s Report

The BSE Inquiry and the vCJD Families

Press Briefing September 2000 Irwin Mitchell Solicitors

“ Insufficient research was undertaken into means of ameliorating the progress of vCJD. In particular, the Families are concerned that the work on Dextran Sulphate 500 and Pentosan Polysulphate undertaken at the ARC Neuropathogenesis Unit [NPU] during the 1970's was not immediately revisited once vCJD had been identified in 1996”.

Research will now assess CJD drug By Karen Allen BBC Health Correspondent March 1 st 2005 The parents of a young woman with the brain disease vCJD have persuaded government researchers to consider the drug their daughter is taking. The High Court gave the go-ahead for the first patient (Jonny Simms) with vCJD to undergo treatment with PPS in December 2002. That patient, Jonathan Simms is now the longest surviving with vCJD. In both the cases of Holly Mills and Jonathan Simms, PPS seems to have slowed the progress of the disease. But without thorough research it is not clear whether this is the normal course of vCJD, about which so little is known, or some effect of the drug. The BBC understands that at least eight UK patients are on the same therapy.

The parents of a young woman with the brain disease vCJD have persuaded government researchers to consider the drug their daughter is taking.

The High Court gave the go-ahead for the first patient (Jonny Simms) with vCJD to undergo treatment with PPS in December 2002. That patient, Jonathan Simms is now the longest surviving with vCJD.

In both the cases of Holly Mills and Jonathan Simms, PPS seems to have slowed the progress of the disease.

But without thorough research it is not clear whether this is the normal course of vCJD, about which so little is known, or some effect of the drug.

The BBC understands that at least eight UK patients are on the same therapy.

Potential diagnostic methods Finding a simple non-invasive technique for accurately confirming diagnosis of BSE and CJD is an ultimate goal. Brain stem function is often measured by monitoring obvious changes in heart rate variability (HRV). One study (2002 – 2004) looked at whether measurements of HRV can be found to be a reliable indicator of disease. This non-invasive measuring technique could offer an inclusive diagnostic approach at the point suspected cases are assessed.

Finding a simple non-invasive technique for accurately confirming diagnosis of BSE and CJD is an ultimate goal. Brain stem function is often measured by monitoring obvious changes in heart rate variability (HRV).

One study (2002 – 2004) looked at whether measurements of HRV can be found to be a reliable indicator of disease. This non-invasive measuring technique could offer an inclusive diagnostic approach at the point suspected cases are assessed.

Heart Rate Variability (HRV) measurements on CJD patients Chris Pomfrett Lecturer in Neurophysiology applied to Anaesthesia (Clinical Scientist) The University of Manchester Manchester Royal Infirmary M13 9WL Co-Workers: Professor Brian Pollard M.D., FRCA, David Glover, B.Sc. vCJD study DoH funded 2002 - June 04 BSE study funded by UK Dept. of Health (£112,000)

 

Conclusions for 2005 HRV may form the basis for a live test for brainstem dysfunction HRV appears to show changes in brainstem function in patients receiving putative therapies for vCJD and GSS In conjunction with DWI, EEG, 14-3-3, PET Scans and MRI, diagnostic methodologies continue to provide clearer indications of the onset and development/progression of TSE’s.

HRV may form the basis for a live test for brainstem dysfunction

HRV appears to show changes in brainstem function in patients receiving putative therapies for vCJD and GSS

In conjunction with DWI, EEG, 14-3-3, PET Scans and MRI, diagnostic methodologies continue to provide clearer indications of the onset and development/progression of TSE’s.

Diagnosis of asymptomatic individuals Prophylactic treatment An in-vivo test will be essential once anti-prion prophylactic treatments are discovered Prophylactic treatments will only be useful in the presence of a simple and efficient in-vivo test.

Effective treatment of prion diseases - Is it possible? Clinical symptoms diagnosis Treatment partially ineffective due to already established brain damage Screening of population at risk Diagnosis of asymptomatic individuals Prophylactic treatment

“ We are Family”   We met by chance via very similar situations   We pass over very important information to each other   We define real friendship   We set many targets and goals   We help integrate Founders and researchers   We spark inspiration   We now globalize what we do   We are important and forge all that we do into the current and next generation whilst fully respecting our predecessors.

 

We met by chance via very similar situations

 

We pass over very important information to each other

 

We define real friendship

 

We set many targets and goals

 

We help integrate Founders and researchers

 

We spark inspiration

 

We now globalize what we do

 

We are important and forge all that we do into the current and next generation whilst fully respecting our predecessors.

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