Detection of protein aggregates in brain and cerebrospinal fluid
derived from multiple sclerosis patients
Hypothesis & Theory ARTICLE Front. Neurol., 02 December 2014 | doi:
10.3389/fneur.2014.00251
Detection of protein aggregates in brain and cerebrospinal fluid derived
from multiple sclerosis patients
imageMonique Antoinette David1,2 and imageMourad Tayebi1,3* 1Mitchell
Center for Alzheimer’s Disease and Related Brain Disorders, Department of
Neurology, University of Texas Houston Medical School, Houston, TX, USA
2Antibody Discovery Laboratory, PrioCam, Houston, TX, USA 3Department of
Pathology and Infectious Diseases, Faculty of Health and Medical Sciences,
University of Surrey, Guildford, UK
Studies of the properties of soluble oligomer species of amyloidogenic
proteins, derived from different proteins with little sequence homology, have
indicated that they share a common structure and may share similar pathogenic
mechanisms. Amyloid β, tau protein, as well as amyloid precursor protein
normally associated with Alzheimer’s disease and Parkinson’s disease were found
in lesions and plaques of multiple sclerosis patients. The objective of the
study is to investigate whether brain and cerebrospinal fluid (CSF) samples
derived from multiple sclerosis patients demonstrate the presence of soluble
oligomers normally associated with protein-misfolding diseases such as
Alzheimer’s disease. We have used anti-oligomer monoclonal antibodies to
immunodetect soluble oligomers in CSF and brain tissues derived from multiple
sclerosis patients. In this report, we describe the presence of soluble
oligomers in the brain tissue and cerebral spinal fluid of multiple sclerosis
patients detected with our monoclonal anti-oligomer antibodies with Western blot
and Sandwich enzyme-linked immunosorbent assay (sELISA). These results might
suggest that protein aggregation plays a role in multiple sclerosis pathogenesis
although further and more refined studies are needed to confirm the role of
soluble aggregates in multiple sclerosis.
Finally, co-morbidities are a recognized feature following autopsy of
patients with PMDs; for instance, both Parkinson’s and AD have been recognized
in same patients. We therefore wanted to assess whether brain homogenates
derived from MS patients displayed PK-resistant prions (Figure 4B) and we also
checked for the presence of Aβ and α-synuclein (data not shown). Brain
homogenates from patients with MS (Secondary progressive) did not display any
presence of PK-resistant prions as assessed by anti-prion antibody and also
failed to demonstrate binding for Aβ and α-synuclein.
Our study shows for the time that protein aggregates detected by
anti-oligomer specific antibodies are associated with MS. The data generated so
far does not allow to reach a substantive conclusion in relation to the
involvement of these proteins aggregates in MS pathogenesis. Protein aggregation
associated with MS has been described previously in a rodent model of MS (16).
Dasgupta and colleagues have demonstrated increased protein aggregation in the
spinal cord of mice with experimental autoimmune encephalomyelitis (EAE). In
their study, they argue that accumulation of misfolded proteins is caused by
increased rate of protein oxidation and reduced proteasome degradation, both
seen in MS (17) and EAE (18, 19).
In conclusion, for the first time, we demonstrate the presence of soluble
oligomers, normally associated with PMDs, in MS tissues and CSF. Although the
pathogenic relevance of these MS associated soluble oligomers to disease process
remains to be investigated, this study sets the ground for further investigating
this relationship. This study proposes a novel alternative in understanding the
pathogenesis of MS.
Physiol Rev. 2009 Oct;89(4):1105-52. doi: 10.1152/physrev.00006.2009.
Prions: protein aggregation and infectious diseases.
Aguzzi A1, Calella AM. Author information 1Institute of Neuropathology,
University Hospital of Zurich, Zurich, Switzerland. adriano.aguzzi@usz.ch
Abstract
Transmissible spongiform encephalopathies (TSEs) are inevitably lethal
neurodegenerative diseases that affect humans and a large variety of animals.
The infectious agent responsible for TSEs is the prion, an abnormally folded and
aggregated protein that propagates itself by imposing its conformation onto the
cellular prion protein (PrPC) of the host. PrPC is necessary for prion
replication and for prion-induced neurodegeneration, yet the proximal causes of
neuronal injury and death are still poorly understood. Prion toxicity may arise
from the interference with the normal function of PrPC, and therefore,
understanding the physiological role of PrPC may help to clarify the mechanism
underlying prion diseases. Here we discuss the evolution of the prion concept
and how prion-like mechanisms may apply to other protein aggregation diseases.
We describe the clinical and the pathological features of the prion diseases in
human and animals, the events occurring during neuroinvasion, and the possible
scenarios underlying brain damage. Finally, we discuss potential antiprion
therapies and current developments in the realm of prion diagnostics.
snip...
Another major unresolved issue is the extent to which the induced
amyloidotic lesions can spread from localized sites of seeding by the inoculum
to other sites within the host. Surprisingly, a recent study reported that
healthy fetal tissue grafted into the brains of Parkinson’s disease patients
acquired cytoplasmic -synuclein-rich Lewy bodies, suggesting that misfolded
-synuclein spreads to healthy cells and acts as a template for the conversion
of native -helices to pathogenic -sheets (299).
Type 2 diabetes is yet another disease whose pathogenesis may involve
ordered protein aggregation. Evidence for this was discovered early on (373) but
was largely forgotten for almost a century. It is now evident that aggregation
of islet amyloid polypeptide (IAPP) is an exceedingly frequent feature of type 2
diabetes. IAPP amyloid damages the insulin-producing -cells within pancreatic
islets and may crucially contribute to the pathogenesis of diabetes (233). It is
unknown, however, whether IAPP deposition simply accrues linearly with IAPP
production, or whether it spreads in a prion-like fashion from one pancreatic
islet to the next.
In summary, the role of protein misfolding and aggregation in various human
diseases has been clearly established in the past decade, yet an important
challenge for the coming years will be to determine whether the prion mechanism
of disease transmission might be operating in other human diseases, some of
which are highly prevalent.
snip...
Immune responses in rapidly progressive dementia: a comparative study of
neuroinflammatory markers in Creutzfeldt-Jakob disease, Alzheimer’s disease and
multiple sclerosis
Katharina Stoeck†, Matthias Schmitz*†, Elisabeth Ebert, Christian Schmidt
and Inga Zerr
Abstract
Immunological responses may contribute to disease progression and clinical
heterogeneity in neurodegenerative dementia, for example, Alzheimer’s disease
(AD) and Creutzfeldt-Jakob disease (CJD). Recently, a rapidly progressive form
of AD (rpAD) has been described. On neuropathological grounds classical AD and
rpAD are not distinguishable at present. All those protein aggregopathies show a
state of chronic inflammation with microglia activation and production of
proinflammatory cytokines. In this context, it is hypothesized that the severity
of the surrounding inflammation substantially contributes to disease progression
and accelerated disease courses as seen in rpAD. Using a cytokine multiplex
array based on Luminex Technology, we studied 17 pro- and anti-inflammatory
cytokines in cerebrospinal fluid (CSF) and serum from patients with classical
dementia (AD) or rapidly progressive dementia (Creutzfeldt-Jakob disease (CJD),
rpAD). For controls, we chose patients with multiple sclerosis (MS) and
non-neurodegenerative diseases. We found a significant and isolated elevation of
proinflammatory cytokines (IL-13, TNF-α and G-CSF) in the serum of rpAD
patients. In CSF, IL-8 and MCP-1 chemokines were significantly elevated in CJD
patients and MCP-1 in AD patients. In conclusion, we found a characteristic
proinflammatory cytokine response in the serum of rpAD patients. It might
explain the more rapidly progressive course of the rpAD subform and can be
helpful in distinguishing between classical AD and rpAD.
Abbreviations Aβ: amyloid beta; AD: Alzheimer’s disease; CJD:
Creutzfeldt-Jakob disease; CSF: cerebrospinal fluid; MS: multiple sclerosis;
PrP: prion protein; rpAD: a rapidly progressive form of Alzheimer’s
disease.
Wednesday, November 13, 2013
Spontaneous Generation of Infectious Prion Disease in Transgenic Mice
***These considerations enable us to hypothesize that the BSE epidemic
could have begun by a random genetic mutation that was able to generate de novo
infectious prions, which were included in meat and bone meal fed to cattle and
then broadly expanded in the cattle population. According to this hypothesis, a
key strategy for controlling BSE would involve preventing cows from consuming
products from cows with spontaneous cases of BSE.***
Tuesday, May 7, 2013
Proteinopathies, a core concept for understanding and ultimately treating
degenerative disorders?
Sunday, February 10, 2013
Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a
Prion-Like Disorder?
Wednesday, May 16, 2012
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion
disease, Iatrogenic, what if ?
Proposal ID: 29403
Wednesday, September 21, 2011
PrioNet Canada researchers in Vancouver confirm prion-like properties in
Amyotrophic Lateral Sclerosis (ALS)
Friday, September 3, 2010
Alzheimer's, Autism, Amyotrophic Lateral Sclerosis, Parkinson's, Prionoids,
Prionpathy, Prionopathy, TSE
Self-Propagative Replication of Ab Oligomers Suggests Potential
Transmissibility in Alzheimer Disease
Received July 24, 2014; Accepted September 16, 2014; Published November 3,
2014
Singeltary comment ;
Sunday, November 23, 2014
Confirmed Variant Creutzfeldt-Jakob Disease (variant CJD) Case in Texas in
June 2014 confirmed as USA case NOT European
‘’The specific overseas country where this patient’s infection occurred is
less clear largely because the investigation did not definitely link him to a
country where other known vCJD cases likely had been infected.’’
Friday, December 5, 2014
SPECIAL ALERT The OIE recommends strengthening animal disease surveillance
worldwide
OIE BSE TSE PRION AKA MAD COW DISEASE ?
‘’the silence was deafening’’ ...tss
TSS
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