Possible Link between SARS-CoV-2 Infection and Parkinson's Disease: The Role of Toll-Like Receptor 4

Abstract

Parkinson's disease (PD) is the most common neurodegenerative motor disorder characterized by selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain, depletion of dopamine (DA), and impaired nigrostriatal pathway. The pathological hallmark of PD includes the aggregation and accumulation α-synuclein (α-SYN). Although the precise mechanisms underlying the pathogenesis of PD are still unknown, the activation of toll-like receptors (TLRs), mainly TLR4 and subsequent neuroinflammatory immune response, seem to play a significant role. Mounting evidence suggests that viral infection can concur with the precipitation of PD or parkinsonism. The recently identified coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of ongoing pandemic coronavirus disease 2019 (COVID-19), responsible for 160 million cases that led to the death of more than three million individuals worldwide. Studies have reported that many patients with COVID-19 display several neurological manifestations, including acute cerebrovascular diseases, conscious disturbance, and typical motor and non-motor symptoms accompanying PD. In this review, the neurotropic potential of SARS-CoV-2 and its possible involvement in the pathogenesis of PD are discussed. Specifically, the involvement of the TLR4 signaling pathway in mediating the virus entry, as well as the massive immune and inflammatory response in COVID-19 patients is explored. The binding of SARS-CoV-2 spike (S) protein to TLR4 and the possible interaction between SARS-CoV-2 and α-SYN as contributing factors to neuronal death are also considered.

Keywords: COVID-19; Parkinson’s disease; SARS-CoV-2; neuroinflammation; synuclein; toll-like receptor 4.

Figure 1

Schematical representation of TLR4 activation in microglia and consequent dopaminergic neuronal damage in the substantia nigra. A number of pro-inflammatory stimuli can promote the activation of the intracellular TLR4 signaling pathway in microglia. Upon infection or injury, DAMPs or PAMPs released in the extracellular milieu via exocytosis from neighboring neurons are sensed by microglial TLR4 for degradation and clearance. If compromised or if prolonged, this process can lead to further inflammatory signaling in which the engagement of myeloid differentiating primary response gene 88 (MyD88) or TIR-domain containing adapter inducing interferon β (TRIF) provokes the activation of downstream signaling cascades that lead to the proteasomal degradation of kB inhibitors (IkB), release, and nuclear translocation of the NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) transcription factor. The transcriptional activation of specific genes induces the release of proinflammatory cytokines, that in turn can cause neuronal damage, pathological modification of α-SYN (monomers, oligomers, and fibrils, truncated and phosphorylated forms), and aggregation in Lewy and neurites bodies—the pathological hallmarks of degenerating neurons in Parkinson’s disease. Endosomal TLRs sense bacterial or viral nucleic acids.

Figure 2

Toll-like receptor 4 (TLR4) signaling cascade resulting from the interaction between TLR4 and SARS-CoV-2 S protein. (a). Schematic diagram of the primary structural proteins of SARS-CoV-2.(b). The interaction between TLR4 and the SARS-CoV-2 S protein can trigger an intracellular TLR4 signaling cascade that can be one of the factors leading to the cytokine storm and neuroinflammation in severe COVID-19 patients. SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2; Coronavirus disease. CD14: cluster of differentiation 14; MD2: myeloid differential protein-2; MyD88: myeloid differentiating primary response gene 88; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; IRAK: interleukin-1 receptor-associated kinases; TRIF: TIR-domain containing adapter inducing interferon β; TRAM: TRIF-related adaptor molecule; TRAF: tumor necrosis factor receptor-associated factor; IFN: interferon.

Figure 3

SARS-CoV-2 neuroinvasion and neuropathogenesis. SARS-CoV-2 may cause the disruption of the BBB integrity to gain access to the CNS. Viral invasion initiates inflammatory signaling involving the activation of microglia and release of abundant levels of proinflammatory cytokines/chemokines, which in turn can disrupt the BBB and increase its permeability. The inflammatory response can cause the neuronal accumulation of α-SYN and neuronal damage. The aggregates of α-SYN released from the neurons can induce microglia activation and initiate a vicious circle. IL: interleukin; TNFα: tumour necrosis factor alpha, IFN-γ: Interferon-gamma; Cox-2; cyclooxygenase-2; NOS: nitric oxide synthase; ROS: reactive oxygen species.

Figure 4

Possible direct interaction between the spike protein and α-sinuclein. (a) SARS-CoV-2 genome organization. Open Reading Frames (ORFs); Envelope (E); Nucleocapside (N); Membrane protein (M). (b) Schematic depiction of α-synuclein structure. N-terminus, NAC (non-amyloid-β component) region, and C-terminus are coloured blue, pink and red, respectively. (NAC). (c) The possible direct interaction between SARS-CoV-2 and α-SYN could start a conformational shift of the monomeric protein and accelerate the formation of toxic multimeric protein species, such as oligomers/protofibrils and fibril aggregates, resulting in neuronal death.

Figure 5

Possible mechanism proposed for α-synuclein aggregation in dopaminergic neurons. The binding of the S protein to the ACE2 receptor mediates the virus entry into dopaminergic cells. In the host cells, the virus can induce endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR) and ubiquitin proteasome system (UPS) activation, leading to impairment of proteostasis, α-SYN aggregation, and neurodegeneration. A similar mechanism can be triggered by SARS-CoV-2-induced TLR4 activation.