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. firstname.lastname@example.org
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.
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.
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
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