Humoral cross reactivity between α-synuclein and herpes simplex-1 epitope in Parkinson's disease, a triggering role in the disease?

Caggiu, Elisa; Paulus, Kai Stephan; Arru, Giannina; Piredda, Rosanna; Sechi, Gian Pietro; Sechi, Leonardo Antonio

doi:10.1016/j.jneuroim.2016.01.007

Cited by 57 publications

(56 citation statements)

References 24 publications

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“…Thus, it has been speculated that influenza virus or Actinobacteria may be involved in the etiology of PD [24][25][26][27]. It has been suggested that molecular mimicry between HSV1 and α-synuclein could foster the progression of PD [28,29]. Also, the possibility that some toxins or fungi can provoke PD has been suggested [30][31][32][33][34].…”

Section: Ivyspringmentioning

confidence: 99%

Parkinson's Disease: A Comprehensive Analysis of Fungi and Bacteria in Brain Tissue

Pisa¹,

Alonso²,

Carrasco³

2020

Int. J. Biol. Sci.

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Parkinson's disease (PD) is characterized by motor disorders and the destruction of dopaminergic neurons in the substantia nigra pars compacta. In addition to motor disability, many patients with PD present a spectrum of clinical symptoms, including cognitive decline, psychiatric alterations, loss of smell and bladder dysfunction, among others. Neuroinflammation is one of the most salient features of PD, but the nature of the trigger remains unknown. A plausible mechanism to explain inflammation and the range of clinical symptoms in these patients is the presence of systemic microbial infection. Accordingly, the present study provides extensive evidence for the existence of mixed microbial infections in the central nervous system (CNS) of patients with PD. Assessment of CNS sections by immunohistochemistry using specific antibodies revealed the presence of both fungi and bacteria. Moreover, different regions of the CNS were positive for a variety of microbial morphologies, suggesting infection by a number of microorganisms. Identification of specific fungal and bacterial species in different CNS regions from six PD patients was accomplished using nested PCR analysis and next-generation sequencing, providing compelling evidence of polymicrobial infections in the CNS of PD. Most of the fungal species identified belong to the genera Botrytis, Candida, Fusarium and Malassezia. Some relevant bacterial genera were Streptococcus and Pseudomonas, with most bacterial species belonging to the phyla Actinobacteria and Proteobacteria. Interestingly, we noted similarities and differences between the microbiota present in the CNS of patients with PD and that in other neurodegenerative diseases. Overall, our observations lend strong support to the concept that mixed microbial infections contribute to or are a risk factor for the neuropathology of PD. Importantly, these results provide the basis for effective treatments of this disease using already approved and safe antimicrobial therapeutics.

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Section: Ivyspringmentioning

confidence: 99%

Parkinson's Disease: A Comprehensive Analysis of Fungi and Bacteria in Brain Tissue

Pisa¹,

Alonso²,

Carrasco³

2020

Int. J. Biol. Sci.

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“…Accordingly, an increase in the incidence of PD has been associated with herpes simplex virus (HSV) and influenza virus infections (Harris, Tsui, Marion, Shen, & Teschke, ; Vlajinac et al., ). Interestingly, cross‐reactivity between a‐syn and an HSV‐1 epitope has been detected in PD patients, suggesting that HSV‐1 could promote an auto‐immune response against a‐syn (Caggiu et al., ). The same group also reported that homologous HSV1 and a‐syn peptide can both stimulate T‐cell responses (with TNF production) in PD patients, further suggesting that HSV‐1 can contribute to disease phenotype (Caggiu et al., ).…”

Section: Infections As Putative Players In the Risk Of Developing Parmentioning

confidence: 99%

Immune system responses in Parkinson's disease: Early and dynamic

Tansey

Romero‐Ramos

2018

Eur J of Neuroscience

115

125

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The neuropathological hallmarks of Parkinson's disease (PD) are the degeneration and death of dopamine‐producing neurons in the ventral midbrain, the widespread intraneuronal aggregation of alpha‐synuclein (α) in Lewy bodies and neurites, neuroinflammation, and gliosis. Signs of microglia activation in the PD brain postmortem as well as during disease development revealed by neuroimaging, implicate immune responses in the pathophysiology of the disease. Intensive research during the last two decades has advanced our understanding of the role of these responses in the disease process, yet many questions remain unanswered. A transformative finding in the field has been the confirmation that in vivo microglia are able to respond directly to pathological a‐syn aggregates but also to neuronal dysfunction due to intraneuronal a‐syn toxicity well in advance of neuronal death. In addition, clinical research and disease models have revealed the involvement of both the innate and adaptive immune systems. Indeed, the data suggest that PD leads not only to a microglia response, but also to a cellular and humoral peripheral immune response. Together, these findings compel us to consider a more holistic view of the immunological processes associated with the disease. Central and peripheral immune responses aimed at maintaining neuronal health will ultimately have consequences on neuronal survival. We will review here the most significant findings that have contributed to the current understanding of the immune response in PD, which is proposed to occur early, involve peripheral and brain immune cells, evolve as neuronal dysfunction progresses, and is likely to influence disease progression.

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“…Among the many pathogen proteins showing sequence homology to antigenic regions of A␤ are those from B. burgdorferi, C. Neoformans, C. pneumoniae, H. pylori, P. gingivalis, and herpes viruses (HSV1, HHV6, and the cytomegalovirus) [80,202]. Cross-reactivity between antibodies to HSV-1 and synuclein (another antimicrobial peptide [160]) has also been experimentally demonstrated [203]. Regardless of the origin of these autoantibodies, their potential to attenuate the antimicrobial effects of A␤ could well contribute to systemic pathogen accumulation, thus rendering cerebral entry more likely.…”

Section: Abrogation Of the Peripheral Antimicrobial Effects Of Aβ By mentioning

confidence: 99%

Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer’s Disease

Carter

2017

ADR

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Diverse pathogens are detected in Alzheimer’s disease (AD) brains. A bioinformatics survey showed that AD genome-wide association study (GWAS) genes (localized in bone marrow, immune locations and microglia) relate to multiple host/pathogen interactomes (Candida albicans, Cryptococcus neoformans, Bornavirus, Borrelia burgdorferri, cytomegalovirus, Ebola virus, HSV-1, HERV-W, HIV-1, Epstein-Barr, hepatitis C, influenza, Chlamydia pneumoniae, Porphyrymonas gingivalis, Helicobacter pylori, Toxoplasma gondii, Trypanosoma cruzi). These interactomes also relate to the AD hippocampal transcriptome and to plaque or tangle proteins. Upregulated AD hippocampal genes match those upregulated by multiple bacteria, viruses, fungi, or protozoa in immunocompetent cells. AD genes are enriched in GWAS datasets reflecting pathogen diversity, suggesting selection for pathogen resistance, as supported by the old age of AD patients, implying resistance to earlier infections. APOE4 is concentrated in regions of high parasitic burden and protects against childhood tropical infections and hepatitis C. Immune/inflammatory gain of function applies to APOE4, CR1, and TREM2 variants. AD genes are also expressed in the blood-brain barrier (BBB), which is disrupted by AD risk factors (age, alcohol, aluminum, concussion, cerebral hypoperfusion, diabetes, homocysteine, hypercholesterolemia, hypertension, obesity, pesticides, pollution, physical inactivity, sleep disruption, smoking) and by pathogens, directly or via olfactory routes to basal-forebrain BBB control centers. The BBB benefits from statins, NSAIDs, estrogen, melatonin, memantine, and the Mediterranean diet. Polymicrobial involvement is supported by upregulation of bacterial, viral, and fungal sensors/defenders in the AD brain, blood, or cerebrospinal fluid. AD serum amyloid-β autoantibodies may attenuate its antimicrobial effects favoring microbial survival and cerebral invasion leading to activation of neurodestructive immune/inflammatory processes, which may also be augmented by age-related immunosenescence. AD may thus respond to antibiotic, antifungal, or antiviral therapy.

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Humoral cross reactivity between α-synuclein and herpes simplex-1 epitope in Parkinson's disease, a triggering role in the disease?

Cited by 57 publications

References 24 publications

Parkinson's Disease: A Comprehensive Analysis of Fungi and Bacteria in Brain Tissue

Parkinson's Disease: A Comprehensive Analysis of Fungi and Bacteria in Brain Tissue

Immune system responses in Parkinson's disease: Early and dynamic

Genetic, Transcriptome, Proteomic, and Epidemiological Evidence for Blood-Brain Barrier Disruption and Polymicrobial Brain Invasion as Determinant Factors in Alzheimer’s Disease

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