Prion-Like+Properties+of+NDDs

Infectious properties of proteins involved in various NDDs as part of Neurodegenerative Diseases Wiki:
 * Homology Between Neurodegenerative Diseases and Infectious Prions **

From HMB300 Neurowiki 2012

Neurodegenerative diseases (NDDs) have a huge impact on the afflicted individual as well as those who care for them. These diseases cause significant impairment in activities of daily living which can greatly decrease the quality of life. Each NDD targets a specific subset of neurons and has its associated factors that play various roles in the pathogenesis of the disease. Typically these associated proteins/factors present themselves as extracellular plaques or intracellular inclusions; the presence of these plaques and inclusions is linked to neuronal death. Recent research has looked at homologies between the infectious properties of prions and that of some proteins in NDDs. Some of these infectious prion qualities include the ability of prions to propagate from cell-to-cell as well as individual to individual. The discovery of various prion-like characteristics of Tau protein, A-β peptide and α-Synuclein (in Tauopathies,Alzheimer’s disease and Parkinson’s diseaserespectively) has been shown in recent years. As a Result, this emerging knowledge of infectious properties of these proteins/factors can help elucidate the complete mechanism of NDD pathogenesis which in turn can greatly aid in the production of available treatments for NDDs (An area that is lacking).

__**..........................................................................................................................**__ > **1.1**The Qualities That Make Prions Infectious >> **1.1.1**Levels/Modes of infectivity > **1.2**Infectious Properties of Tau Protein >> **1.2.1**Endogenous Conversion & Seeding Properties >> **1.2.2**Transmission Properties > **1.3**Infectious Properties of A-β Peptide >> **1.3.1**Seeding and Self-Propagation Properties of A-β >> **1.3.2**Transmission Properties > **1.4**Infectious Properties of α-Synuclein >> **1.4.1**Help of Gut Nervous System in PD Pathogenesis > **1.5**Possible Implication of an Infectious-theory of NDDs ||  The Qualities That Make Prions Infectious
 * **Table of Contents **

When looking at ‘infection’ as a concept, it is quite easy to overlook the characteristics that define whether or not an entity can be deemed infectious. The classical understanding of infection-related pathology applied to the area of microbiology which encompassed viruses, bacteria and fungi. Thus, with the discovery of prions and the subsequent generation of the protein-only hypothesis (in the last decade), there has been a strong shift in the understanding of ‘infection’ and the entities that are capable of infecting. The idea that a single protein had infectious properties (which were only previously seen at the organismallevel) and the capacity to transmit at different levels (cellular/individual/species) has become a gateway in many areas of research; many groups that study NDDs are trying to see if some of the proteins/factors related to their specific neurodegenerative disease contain similar infectious characteristics. [Note: Although there has been much evidence in the past decade to support the protein-only hypothesis, many researchers have generated gainst the hypotheses and thus, are reluctant to believe it].

 **Levels/Modes of Infectivity **

 It is important to look at the different levels/modes of infectivity that prions are capable of to see if homologous characteristics exist with the proteins/factors seen in some NDDs. The characteristics or properties that make prions infectious are   These characteristics are primarily what make prions ‘infectious’. Recent studies have discovered many of these characteristics are possessed by proteins that are associated with various neurodegenerative diseases.
 * The ability of the disease conformation (Prp-sc) to convert endogenous form (normal-Prp-c) into the disease form via template directed refolding; and the ability of the disease conformation to have the ability to ‘seed’ (seeded nucleation).** [4] **
 * The ability of the disease conformation to transmit prion-disease between cells of the gut, spleen, lymph nodes, and the central nervous system; and the ability to transmit between these organs (Cell/organ level transmission).
 * The ability of prion disease to transmit between individuals of the same species (species level transmission) such as Kuruwhich can be seen in cultures practicing cannibalistic behaviour. **[6] **
 * The ability of prion disease to transmit between species (species level transmission) which can typically be seen with Variant Creutzfeldt–Jakob disease (v-CJD) which can arise following ingestion of bovine tissue infected with bovine-spongiform-encephalitis (or mad cow disease).

<span style="font-family: Cambria,serif; font-size: 14pt;"> Infectious Properties of Tau Protein

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Tau is a microtubule-associated protein associated with Alzheimer’s disease and a group of other neurodegenerative diseases called Tauopathies. Aberrant function of tau protein (either arising via genetics or environmental factors) results in the accumulation of tau in intracellular inclusions called neurofibrillary tangles. This tau pathology observed in Alzheimer’s disease and other Tauopathies is seen to progressively spread throughout the CNS via neighbouring neural connections. This spreading observation is characteristic of prion pathology <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">(transmissible at the organ/individual level), and has sparked research in areas looking to see if tau protein has other prion-like pathological characteristics. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: Cambria,serif; font-size: 12pt;"> **<span style="font-family: Cambria,serif; font-size: 12pt;">Endogenous Conversion & Seeding Properties ** <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> The fibrils (secondary structures) formed by mutant tau protein (P301L/V337M) and wild-type tau protein are markedly different. Tau protein has been shown to share homology with prion proteins in terms of its ability to convert endogenous forms into disease conformations. This ability to convert good-to-bad has been shown in studies that looked at incubating different forms of tau with normal wild-type tau.Typically when incubating wild-type tau fibrils with wild-type monomeric tau protein, the result is that the monomeric wild-type proteins form a secondary fibril structure with wild-type morphology.**<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[12] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> However Incubation of mutant tau-fibrils with monomeric wild-type tau protein was shown to convert the monomeric wild-type proteins into a secondary structure with mutant-fibril morphology. **<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[12] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> These converted tau-fibrils (termed WT* fibrils) were also shown to behave in a mutant fibril-like manner (became resistant to sonication). **<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[12] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Additionally, tau aggregates display further prion-like characteristics in terms of seeding capability. Seeding (as the name implies) is the ability of a factor to travel and seed or ‘colonize’ an environment. This exact seeding capability is shown with misfolded tau aggregates having the ability to be taken up by cells; which then results in further misfolding and aggregation of tau within these cells. **<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[9] **

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> **<span style="font-family: Cambria,serif; font-size: 12pt;">Transmission Properties ** <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> There are different levels of transmission that have been associated with prion proteins. The ability of prions to transmit at the cellular level is mirrored by tau protein as seen by the spread of tau pathology in Alzheimer’s disease and other Tauopathies such as argyrophilic grain disease (AGD).

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> Prions also have the ability to transmit at both the individual level as well as the species level. **<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[6] ****<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[7]  **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Recent evidence suggests that individual and species level transmission can also be seen with tau protein. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> Using transgenic mice one team showed the ability of tau protein to transmit between two individuals of the same species. They showed this by taking brain extracts from transgenic mice (P301S) that express mutated human tau, and injected into transgenic mice expressing human wild-type tau (ALZ17). <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> The P301 transgenic mice spontaneously develop tau pathology whereas the ALZ17 mice do not develop tau pathology. With this model they showed that the pathology associated with the P301S mouse was able to dev <span style="font-family: 'Times New Roman',Times,serif; font-size: 12pt;">elop in <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">the ALZ17 mice that were injected with the brain extracts. **<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[15] **

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Additionally, the same group also observed tau proteins having species level transmission capabilities. Using a similar model, they injected brain extracts from the same P301S transgenic mouse expressing mutated human tau into normal non-humanized, non-transgenic C57/BL6 mice that express mouse tau. **<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[15] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> They saw that the C57/BL6 mice developed tau pathology proposing that tau protein had the ability to transmit pathology at a species level similar to that of prions. **<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[15] **

<span style="font-family: Cambria,serif; font-size: 14pt;"> Infectious Properties of A-β Peptide1.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Like tau protein, Amyloid-β peptide is a factor associated with Alzheimer’s disease. Unlike tauopathies however, where tau protein is the causative factor of the pathology; in Alzheimer’s disease the tau pathology is one of the results stemming from a dysfunction of A-β peptide. **[16]** Dysfunction of A-β peptide progressively accumulate resulting in extracellular plaque formation. The progressive spread of A-β pathology in AD suggests a possible prion-like mechanism.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> **<span style="font-family: Cambria,serif; font-size: 12pt;">Seeding and Self-Propagation Properties of A-β ** <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> A-β Peptide has been shown to contain prion-like seeding and self-propagation properties. In terms of seeding ability, studies have been performed by implanting stainless steel wires into the hippocampus of APP23 transgenic mice. These wires were coated with very minimal amounts of aggregated A-β brain extracts. It was shown that in these mice, after 4 months, in addition to a strong A-β staining at and around the hippocampal wire site; there were also staining of A-β at distant areas throughout the dentate gyrus. This seeding ability of aggregate A-β suggests that there is homology between it and prions.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> The self-propagation property of A-β is another shared homology with prions. Studies have shown that misfolded forms of A-β will promote aggregation which in turn can lead to pathology. Furthermore, other studies have shown that in a controlled in-vitro setting, there is cellular up take of extracellular A-β peptide which results in accumulation intracellular A-β peptide at higher concentrations than extracellular suggesting that there is a propogation/seeding mechanism taking place.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> **<span style="font-family: Cambria,serif; font-size: 12pt;">Transmission properties ** <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> A-β exhibits a similar prion-like capacity to transmit between individuals of the same species. This property can be observed with experiments involving intra-cerebral infusion of brain extracts from Alzheimer patients into APP transgenic mice that express human A-β peptide. These transgenic mice will not develop A-β peptide associated pathology spontaneously. However, in the mice that received the extracts, the A-β peptide associated pathology such as extracellular plaques (Alzheimer’s pathology in mice) were seen.**<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[21] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Interestingly, using peripheral intraperitoneal injections instead of direct intracerebral injections also recapitulated the same A-β pathology observed (albeit with a longer chase period).

<span style="font-family: Cambria,serif; font-size: 12pt;"> Infectious Properties of α-Synuclein

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> Parkinson’s disease is characterized by pathological presentations of Lewy bodies which consist primarily of the protein α-Synuclein and other unsteady factors. Like tauopathies and Alzheimer’s disease, the pathological presentation and progression of Parkinson’s disease (and α-Synuclein) originates at a focal point and gradually spreads in a prion-like mechanistic fashion.**<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[23] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">This idea of α-Synuclein having prion-like proteinopathy can be strikingnly apparent when observing a host to graft spread of Lewy body pathology in Parkinson’s disease patients that received dopaminergic implantations a decade prior to death.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> **<span style="font-family: Cambria,serif; font-size: 12pt;">Help of Gut Nervous System in PD Pathogenesis ** <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> In 2005 a group of neuroscientists decided to see if there may be a link between the gut nervous system and α-Synuclein pathology. They found α-Synuclein inclusions in the submucosal Meissner plexus of the enteric nervous system. With this finding they postulated that some sort of environmental insult may initiate the α-Synuclein misfolding pathology seen in Parkinson’s disease. They then proposed a mechanism of Parkinson’s pathology involving a model where the pathology initiates in the enteric nervous system and travels via vagal nerves to the central nervous system to establishing itself into the characteristic CNS pathology seen in Parkinson’s disease patients. These findings led to the development of the dual-hit hypothesis in subsequent years. <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> The dual-hit hypothesis of Parkinson’s disease pathology suggests that the origin of Parkinson’s disease occurs at the nose and gut. Nasal inhalation and swallowing of a neurotrophic pathogen that establishes itself in the gut can go on to producing α-Synuclein misfolding in the enteric nervous system. And this α-Synuclein pathology is then transmitted to the CNS via vagus nerves.**<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[26] ****<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[27]  **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">Furthermore, the pesticide rotenone which is used in the laboratory setting is a comment vehicle used to induce Parkinson’s disease pathology in rats. Rotenone is injected intraperitoneally, which can induce a Parkinson-like pathology. This suggests an environmental-related mechanism of Parkinson disease induction which helps support the dual-hit hypothesis.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> <span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> In addition to the help of the gut nervous system in Parkinson pathogenesis, the seeding capability of α-Synuclein was also observed. One group showed that the intracellular α-Synuclein-associated Lewy body pathology seen in Parkinson’s Disease can be activated by introducing exogenous α-Synuclein fibrils (pathological version) into cells overexpressing α-Synuclein.**<span style="background-color: #ffffff; font-family: 'Times New Roman',serif; font-size: 80%; vertical-align: super;">[29] **<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> This suggests that aberrant α-Synuclein has seeding abilities, and can produce pathology if present in cells.

<span style="font-family: Cambria,serif; font-size: 14pt;"> Possible Implication of an Infectious-theory of NDDs

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;">The main goal of research in the field of neurodegenerative diseases is to develop a clear understanding of disease pathogenesis. With a strong fundamental understanding of how these diseases develop and progress, the road to making novel therapeutics and treatments will become less obstructed. Thus, with the recent understanding of a possible prion-like infection mechanism in diseases such as Tauopathies, Alzhiemer’s, and Parkinsons is a first step in choosing the right path in therapeutic development. At present, the idea that these diseases are like infections is a huge advantage since these diseases can be treated like infections rather than the current cellular component-dysfunction model that has so far failed in developing therapies.

<span style="font-family: 'Times New Roman',serif; font-size: 12pt;"> **<span style="color: #17365d; font-family: Calibri,sans-serif; font-size: 22pt;">References: **