Immune system may mount an attack in Parkinson’s disease | National Institutes of Health (NIH)

Immune system may mount an attack in Parkinson’s disease | National Institutes of Health (NIH): "A research team led by David Sulzer, Ph.D., professor of neurology at Columbia University in New York City and Alessandro Sette, Dr.Biol.Sci., professor of infectious diseases at the La Jolla Institute for Allergy and Immunology in California, examined the role of T cells in PD.

Drs. Sulzer and Sette, along with their colleagues, collected blood samples from 67 individuals with Parkinson’s disease and 36 healthy controls. Immune cells were extracted from the samples and mixed with portions of the alpha-synuclein protein, which accumulates in the brains of people with PD and can result in cell death.

They found that T cells from people with PD responded to the presence of alpha-synuclein to a much greater degree than those gathered from the control group.

In particular, two regions of alpha-synuclein evoked reactions from T cells: a section that often contains mutations linked with PD, and a portion undergoing a chemical change that can lead to accumulation of the protein in the brain.  "

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Human serum antibodies against EBV latent membrane protein 1 cross-react with α-synuclein.

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Study finds link between upper GI infections and protein (synuclein) implicated in Parkinson’s disease

 "Acute and chronic infections in a person's upper gastrointestinal tract appear to be linked to Parkinson's disease, say scientists at Georgetown University Medical Center and their collaborators at the National Institutes of Health and other institutions.

Their study, published in the Journal of Innate Immunity, finds that alpha-Synuclein (αS), the protein implicated in Parkinson's disease and other forms of neurodegenerative diseases, is released when an infection occurs in the upper GI tract (the esophagus, stomach, and duodenum) inducing an immune response as part of the body's innate immune system. The researchers say that these findings suggest that frequent or chronic upper GI infections could overwhelm the body's capacity to clear αS, leading to disease."



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• Could "Advanced Probiotics" Soon Treat Parkinson's Disease?

Effects of titanium dioxide nanoparticles on α-synuclein aggregation and the ubiquitin-proteasome system in dopaminergic neurons. - PubMed - NCBI

Dopaminergic neurons (PC12 cells) were treated with different doses of titanium dioxide nanoparticles (TiO2-NPs), to investigate their effects on α-Synuclein (α-Syn) aggregation and their mechanism of action. Western blotting and immunofluorescent staining were performed. Exposure to TiO2-NPs increased α-Syn expression (p < 0.05) and induced dose-dependent α-Syn aggregation. Pretreatment with N-acetylcysteine partially inhibited α-Syn expression induced by a 200 μg/ml dose of TiO2-NPs. TiO2-NPs reduced the expressions of parkin and ubiquitin C-terminal hydrolase protein, and were associated with oxidative stress in PC12 cells. Dysfunction of the ubiquitin-proteasome system also contributed to α-Syn aggregation. The potentially neurotoxic TiO2-NPs may cause Parkinson's disease



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Functional characterization of alpha-synuclein protein with antimicrobial activity.

Alpha-synuclein (α-Syn), a small (14 kDa) protein associated with Parkinson's disease, is abundant in human neural tissues. α-Syn plays an important role in maintaining a supply of synaptic vesicles in presynaptic terminals; however, the mechanism by which it performs this function are not well understood. In addition, there is a correlation between α-Syn over-expression and upregulation of an innate immune response. Given the growing body of literature surrounding antimicrobial peptides (AMPs) in the brain, and the similarities between α-Syn and a previously characterized AMP, Amyloid-β, we set out to investigate if α-Syn shares AMP-like properties. Here we demonstrate that α-Syn exhibits antibacterial activity against Escherichia coli and Staphylococcus aureus. In addition, we demonstrate a role for α-Syn in inhibiting various pathogenic fungal strains such as Aspergillus flavus, Aspergillus fumigatus and Rhizoctonia solani. We also analyzed localizations of recombinant α-Syn protein in E. coli and Candida albicans. These results suggest that in addition to α-Syn's role in neurotransmitter release, it appears to be a natural AMP.

Alpha-synuclein expression restricts RNA viral infections in the brain. - PubMed - NCBI

We have discovered that native, neuronal expression of alpha-synuclein (Asyn) inhibits viral infection, injury, and disease in the central nervous system. Enveloped RNA viruses such as West Nile virus (WNV) invade the central nervous system (CNS) and cause encephalitis; yet, little is known about the innate neuron-specific inhibitors of viral infections in the CNS. Following WNV-infection of primary neurons, we found that Asyn protein expression is increased. Infectious viral titer of WNV and Venezuelan equine encephalitis virus (VEEV) TC83 in the brains of Asyn knockout mice exhibited a mean increase of 10(4.5) infectious viral particles compared to wild-type and heterozygote littermates. Asyn knockout mice also exhibited significantly increased virus-induced mortality compared to Asyn heterozygote or homozygote control mice. Viral-induced Asyn localized to perinuclear, neuronal regions expressing viral envelope protein and the ER-associated trafficking protein, Rab1. In Asyn knockout primary neuronal cultures, ER signaling pathways known to support WNV replication are significantly elevated before and during viral infection compared to neurons expressing Asyn. We propose a model in which virus-induced Asyn localizes to ER-derived membranes, modulates virus-induced ER-stress signaling, and inhibits viral replication, growth, and injury in the CNS. These data provide a novel and important functional role for native

alpha-synuclein expression, a protein that is closely associated with the development of Parkinson's disease.

IMPORTANCE: Neuroinvasive viruses such as West Nile
virus are able to infect neurons and cause severe disease such as

encephalitis, infection of brain tissue. Following viral infection in the central nervous system only select neurons are infected, implying that neurons exhibit innate resistance to viral infections. We discovered that native neuronal expression of alpha-synuclein inhibited viral infection in the central nervous system.

When the gene for alpha-synuclein was deleted, mice exhibited significantly decreased survival, markedly increased viral growth in the brain, and evidence

of increased neuron injury. Virus-induced alpha-synuclein localized to

intracellular neuron membranes, and in the absence of alpha-synuclein expression, specific endoplasmic reticulum stress signaling events were significantly

increased. We describe a new neuron-specific inhibitor of viral infections in the central nervous system. Given the importance of alpha-synuclein as a cause of

Parkinson's disease, these data also ascribe a novel functional role for native

expression of alpha-synuclein in the CNS.

Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats -

The cellular hallmarks of Parkinson’s disease (PD) are the loss of
nigral dopaminergic neurons and the formation of α-synuclein-enriched
Lewy bodies and Lewy neurites in the remaining neurons. Based on the
topographic distribution of Lewy bodies established after autopsy of
brains from PD patients, Braak and coworkers hypothesized that Lewy
pathology primes in the enteric nervous system and spreads to the brain,
suggesting an active retrograde transport of α-synuclein (the key
protein component in Lewy bodies), via the vagal nerve. This hypothesis,
however, has not been tested experimentally thus far. Here, we use a
human PD brain lysate containing different forms of α-synuclein
(monomeric, oligomeric and fibrillar), and recombinant α-synuclein in an
in vivo animal model to test this hypothesis. We demonstrate that
α-synuclein present in the human PD brain lysate and distinct
recombinant α-synuclein forms are transported via the vagal nerve and
reach the dorsal motor nucleus of the vagus in the brainstem in a
time-dependent manner after injection into the intestinal wall. Using
live cell imaging in a differentiated neuroblastoma cell line, we
determine that both slow and fast components of axonal transport are
involved in the transport of aggregated α-synuclein. In conclusion, we
here provide the first experimental evidence that different α-synuclein
forms can propagate from the gut to the brain, and that
microtubule-associated transport is involved in the translocation of
aggregated α-synuclein in neurons.

Genetic mutation (synuclein) increases risk of Parkinson’s disease from pesticides

“For the first time, we have used human stem cells derived from Parkinson’s disease patients to show that a genetic mutation combined with exposure to pesticides creates a ‘double hit’ scenario, producing free radicals in neurons that disable specific molecular pathways that cause nerve-cell death,” says Stuart Lipton, M.D., Ph.D., professor and director of Sanford-Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research and senior author of the study. -  

Genetic evidence that new therapies targeting Synuclein in Parkinson's disease may cause harm

 "NorthShore University HealthSystem (NorthShore) and Mayo Clinic researchers have partnered on a study that shows genetic and clinical evidence that therapies targeting the expression of alpha-synuclein -- a gene whose function is involved in the development and progression of Parkinson's disease -- may accelerate disease progression and increase the risk of physical incapacitation and dementia. If replicated, the findings will have profound implications for therapies under development for Parkinson's disease."

Mechanism that leads to sporadic Parkinson's disease identified

Exposure to toxins associated with Parkinson's can increase the abundance of a longer transcript form of alpha-synuclein, which is more toxic.

Parkinson’s: Thinking Outside the Brain’s Black Box - AlzForum Alzheimer Research News

This is a nice review of  Braak and Del Tredici's work suggesting that Parkinson's disease is likely to have a viral or pathogenic origin, starting in the periphery  - rendered all the more likely by the knowledge that both influenza (Jang et al, 2009)  and helicobacter pylori infection can kill substantia nigra neurones.

Parkinson's disease genes risk factors and pathways 

Expression of human A53T alpha-synuclein in the rat substantia nigra (modelsParkinson's disease)

Expression of human A53T alpha-synuclein in the rat substantia nigra using a novel AAV1/2 vector produces a rapidly evolving pathology with protein aggregation, dystrophic neurite architecture and nigrostriatal degeneration with potential to model the pathology of Parkinson's disease.

Detection of elevated levels of {alpha}-synucleinoligomers in CSF from patients with Parkinson disease.