Parkinson’s disease (PD) is a neurological degenerative disorder characterized by
loss of dopaminergic neurons in the substantia nigra (SN) and intracellular inclusions
called Lewy bodies and Lewy tangles, composed mainly by aggregates of α-synuclein.
Braak et al. (2003) proposed that the olfactory epithelium and intestines are the
anatomical sites where PD initiates; as pathological aggregates of α-synuclein are
detected in these tissues in very early or prodromal PD. In this scenario, α-synuclein
seems to reach the central nervous system (CNS) by axonal transport through the sympathetic
nervous system, the glossopharyngeal and vagus nerves as well as the olfactory pathways
(Braak et al., 2003).
Currently a large amount of information on how α-synuclein propagates within the nervous
system has been accumulated. Abnormal aggregates of α-synuclein in the form of fibril
seem to spread within the central nervous system in a “prion-like” fashion; where
fibrillar α-synuclein function as a template for normal endogenous α-synuclein, leading
to progressive aggregation and propagation throughout neurons. However, there are
still unanswered questions on how and why α-synuclein undergoes initial aggregation
in seemingly normal tissues.
The etiology of PD is only partially understood, but it seems to be related to factors
promoting initial abnormal aggregates of α-synuclein. Currently, a conceptual model
including “triggers”, “facilitators” and “aggravators” has been proposed to explain
the role of several of these factors in diverse phases of the disease (Johnson et
al., 2019). Among “triggers”, head trauma, environmental toxins and viral infections
are mainly recognized (Johnson et al., 2019). These “triggers” affect tissues that
are exposed to external influences, such as the nasal and intestinal epithelium; they
are believed to act years or decades before the onset of degeneration of dopaminergic
neurons in the SN. The onset of pathology in the gut and olfactory pathways would
explain the chronic constipation and the olfactory dysfunction frequently preceding
the beginning of motor symptoms in these patients by many years. Considering genetic
risk factors, it has been estimated that they represent between 26% and 36% of the
risk for PD; moreover, genome-wide association studies have identified 78 genetic
loci associated with PD, many of them located close to genes involved in immunological
functions and the lysosomal-autophagy pathway (Tilusiak et al., 2019). For example,
enrichment analysis combining genome-wide association studies and expression Quantitative
Trait Loci data has shown an association with the 6p21 loci containing multiple HLA-MHC-II
genes. Patients with PD seem to have specific immune annotations variants in primary
T lymphocytes from the blood, rather than in specific brain cells as observed in patients
with schizophrenia. This information suggests that a large proportion of the variance
explaining the etiology of PD is related to a complex interaction between environmental
and genetic factors.
Epidemiological and experimental evidence linking viruses with PD: Some viral infections
are known to produce post-encephalitic parkinsonism as part of direct involvement
of the CNS; however, the question is whether viruses can contribute to the pathogenesis
of PD. Case-control studies and epidemiological surveillances have identified a relationship
between some previous viral infections and enhanced risk of PD; these associations
would include influenza virus, herpes simplex virus, hepatitis B virus and hepatitis
C virus (HCV) among others; however, only infection with HCV has shown a consistent
association with PD in meta-analyses (Wang et al., 2020).
Besides this clinical and epidemiological evidence, there are experimental studies
showing that viruses may alter the expression and aggregation of α-synuclein in infected
cells. In 42 children with a mean age of 12.4 years, suffering gastric and duodenal
inflammation or intestinal allograft recipients, studied for levels of α-synuclein
in immunostained endoscopic biopsies; gastrointestinal infections with norovirus lead
to up-regulation of α-synuclein in the enteric nervous system (Stolzenberg et al.,
2017); such increased expression of α-synuclein would lead to increased aggregation,
even if the protein is not intrinsically abnormal. Enhanced phosphorylation of α-synuclein
promoting its aggregation has been observed in C57BL/6J mouse infected with influenza
virus A/Vietnam/1203/04 H5N1, along with loss of dopaminergic neurons in the SN (Jang
et al., 2009). The virus is capable to travel from the peripheral to the central nervous
system in mice and activate microglia (Jang et al., 2009). A similar finding was observed
in CD-1 mice infected with Western Equine Encephalitis Virus with the extent of viral
replication controlled using passive immunotherapy, where increased amounts of phosphorylated
α-synuclein in the serine 129 residue were found in the entorhinal cortex, hippocampus
and basal midbrain (Bantle et al., 2019). More recently, it has been shown that replication
of influenza virus (H1N1) can cause severe disturbances in proteostasis (the fine-tuned
balance of cellular protein levels) inducing seeds of aggregated α-synuclein in Lund
human mesencephalic dopaminergic cells in vitro, but not of TDP-43 or tau protein
suggesting a selective effect for α-synuclein (Marreiros et al., 2020). Reinforcing
the hypothesis that viral infections can trigger the early pathological findings of
PD; however, these studies need confirmation under similar experimental conditions.
Moreover, in the majority of these studies, inflammation and abnormal neuro-pathological
findings persisted after resolution of the infection, suggesting a “hit and run” mechanism
of damage by the studied viruses; this feature would limit the discovery of a similar
mechanism in humans.
Viruses can also induce robust inflammatory responses, which can contribute to the
pathogenesis of PD by a “hit and run” mechanism of damage to the CNS, occurring when
the virus has been cleared and it is no longer possible to find the viral genome or
antigens in the affected tissue. Experimental infections to rodents with influenza
H1N1 virus, Japanese Encephalitis Virus and Western Equine Encephalitis Virus produced
marked gliosis with microglial activation in the hippocampus and SN leading to the
pathological and motor findings of PD (Bantle et al., 2019). Moreover, the systemic
inflammatory response elicited by some virus such as HCV is believed to increase the
risk of PD by damaging dopaminergic neurons; in the latter case, epidemiological studies
and meta-analyses have shown a decreased incidence of PD in individuals receiving
interferon-based antiviral treatment regimens against HCV at 5-year follow-up (Lin
et al., 2019); however, it is not entirely clear whether this observed risk reduction
is related to a reduced inflammatory response or a direct antiviral effect on potentially
neurotropic HCV or both mechanisms.
Interestingly, α-synuclein has shown to inhibit viral infections limiting the injury
to the CNS. There is evidence that α-synuclein has properties similar to the antimicrobial
peptides as it has antibacterial activity against E. coli, S. aureus and some fungal
pathogens in the brain. Experimental infections with West Nile virus in α-synuclein-knockout
mice have shown to produce a robust increase in viral particles with enhanced neuronal
injury leading to shortened survival compared with wild-type or heterozygote mice
(Beatman et al., 2015). Moreover, an increase in the amount of monomeric and oligomeric
α-synuclein has shown a consistent chemoattractant effect on neutrophils and monocytes
following infection with norovirus (Stolzenberg et al., 2017), suggesting that such
inflammatory response is common after exposure to this type of infection. Whether
the enhanced expression and inflammatory response induced by the neuro-protective
effects of α-synuclein may contribute to its own aggregation is a contentious possibility
that requires further investigation.
In summary, epidemiological, clinical and experimental evidence suggests a link between
viral infections and the risk of PD. This could be caused by a direct effect in α-synuclein
expression and phosphorylation, through an inflammatory response elicited by the infection
or a complex interplay between both. Another potentially related mechanism would implicate
an impaired degradation of intracellular proteins induced by the virus. This mechanism
has been proposed as relevant in the pathogenesis of PD, which leads to an overload
and accumulation of misfolded α-synuclein.
Can viruses impairing cellular degradation mechanisms have a role in the pathogenesis
of PD? Coronaviruses (CoVs) such as Middle East Respiratory Syndrome, mouse hepatitis
virus, and SARS-CoV (a virus causing an outbreak in China in year 2002) seem to alter
proteostasis by diverting the cellular quality control pathways that degrade misfolded
proteins in order to replicate its viral genome, making cells vulnerable to decreased
clearance of aggregated proteins; this is achieved by hijacking the autophagy machinery
by generating viral double membrane vesicles (DMVs) in the infected cytoplasm that
are unable to fuse with lysosomes, the cellular organelle that ultimately destroys
proteins (Reggiori et al., 2010). Besides CoVs, coxsackievirus B3, poliovirus and
HCV can also induce DMVs in infected cells, facilitating viral replication and assembly.
It is unclear whether this pathogenic mechanism can also account for the increased
risk of PD conferred by HCV infections.
Lipidation of the cytosolic microtubule associated light chain 3 I (LC3-I) protein
generating LC3-II is considered a key event in the induction of autophagy. This protein
is essential for the formation of structures similar to DMVs called autophagosomes.
It has been proposed that certain viruses such as SARS-CoV and HCV may recruit non-lipidated
LC3 in DMVs. Interestingly, a number of genes causing monogenic inherited forms of
PD express proteins implicated in control of autophagy and endomembrane trafficking;
among these proteins, LRRK2 has a special relevance as it is the most common hereditary
cause of monogenic inherited PD. Evidence suggests that some LRRK2 mutations may decrease
lipidation of LC3-I resulting in accumulation of autophagic vacuoles (Roosen and Cookson,
2016). It can be hypothesized that individuals with LRRK2 mutations may be vulnerable
to the effects of viruses that sequestrate LC3-I, such as CoVs or HCV, as this would
cause an additive effect with even lower levels of LC3-II, further reducing elimination
of cellular debris. If the cell survives to the infection, the damaged cellular mechanism
for protein degradation may turn the cell even more vulnerable for accumulation of
misfolded proteins such as α-synuclein.
In recent months, infection with “Severe Acute Respiratory Syndrome Coronavirus-2”
(SARS-CoV-2) has scaled into a pandemic level threatening health-care systems around
the world owing to its capacity to cause respiratory failure. SARS-CoV-2 can also
cause diarrhea and neurological symptoms including hyposmia, suggesting that the virus
has tropism for the gastrointestinal tract and the nervous system. The neurotropic
effects of SARS-CoV-2 may be mediated by its S-protein binding to the angiotensin-converting
enzyme type-2 receptor, which is highly expressed in neurons. Although the full biology
of SARS-CoV-2 is still to be elucidated, the molecular reminiscent between this virus
and other CoVs suggests that they may cause similar derangements in cell structures
and protein processing.
Conclusions: The role of viruses in the pathogenesis of PD is still controversial.
The clinical and epidemiological evidence supports a pathogenic role for HCV; this
virus shares similar features to CoVs as both can elicit a strong immunological response,
have neurotropic potential and use the DMVs system for replication, potentially impairing
the cellular autophagy system. Although common viruses affecting humans such as norovirus
and influenza virus have been shown to increase the expression and aggregation of
α-synuclein, this evidence remains in an experimental level and it is unclear if they
can increase the risk of PD. Whether individuals with underlying monogenic inherited
mutations causing PD may have a higher risk to develop PD when they encounter viral
“triggers” is a hypothesis that would require further assessments, as PD seems to
result from a complex interplay between environmental and genetic mechanisms.