Iron Dysregulation and Inflammagens Related to Oral and Gut Health Are Central to the Development of Parkinson's Disease

Abstract

Neuronal lesions in Parkinson's disease (PD) are commonly associated with α-synuclein (α-Syn)-induced cell damage that are present both in the central and peripheral nervous systems of patients, with the enteric nervous system also being especially vulnerable. Here, we bring together evidence that the development and presence of PD depends on specific sets of interlinking factors that include neuroinflammation, systemic inflammation, α-Syn-induced cell damage, vascular dysfunction, iron dysregulation, and gut and periodontal dysbiosis. We argue that there is significant evidence that bacterial inflammagens fuel this systemic inflammation, and might be central to the development of PD. We also discuss the processes whereby bacterial inflammagens may be involved in causing nucleation of proteins, including of α-Syn. Lastly, we review evidence that iron chelation, pre-and probiotics, as well as antibiotics and faecal transplant treatment might be valuable treatments in PD. A most important consideration, however, is that these therapeutic options need to be validated and tested in randomized controlled clinical trials. However, targeting underlying mechanisms of PD, including gut dysbiosis and iron toxicity, have potentially opened up possibilities of a wide variety of novel treatments, which may relieve the characteristic motor and nonmotor deficits of PD, and may even slow the progression and/or accompanying gut-related conditions of the disease.

Keywords: Parkinson’s disease; amyloid and α-synuclein; bacteria; gingipains; iron; lipopolysaccharides.

Figure 1

An overview of Parkinson’s disease (PD): what do we know from the literature? (1) Traditional focus on a synuclein-centric and neuro-centric- approach, where researchers predominantly focused for the origins of PD in the central nervous system (CNS). Recently, there has been a shift in focus to look closer at the role of both (2) lifestyle and (3) environmental factors that result in (4) innate immune activation, in the development of PD; these 3 factors (depicted in (2), (3) and (4), directly impact and play a significant role in PD brain neurodegeneration. (5) Inflammagens and inflammatory cytokines from the periphery can translocate to the brain.

Figure 2

Interactions in a PD neuron between mitochondria, lysosomes, iron, and α-Syn production and ultimately proteasomal dysfunction, oxidative stress and apoptosis (adapted from [20]). The figure illustrates the interplay between mitochondria and lysosomes during the apoptotic cell death that characterizes the death of neurons in the substantia nigra that is the hallmark of PD. The location of receptors like the TLR and IL-1 receptors and the metal ion transporter 1 are shown. These receptors and transporter are known to bind bacterial inflammagens, IL-1, and Fe²⁺. In PD, there is also a loss of neuromelanin in the substantia nigra, and this could lead to enhanced calcium messaging. These molecules play a fundamental role in the downstream activation of inflammation and oxidative stress, and ultimately play a crucial role in α-Syn and Lewy body formation.

Figure 3

Parkinson’s disease: a continuum or distinct events hypothesis? The condition is characterized by the presence of (1) predisposing genetic, environmental, and lifestyle factors that together contribute to both (2) systemic and neuro-inflammation. (3) Autonomic dysfunction and a (4) dysregulated bidirectional signalling system and (5) α-Syn aggregation are associated with (6) motor and dopaminergic neuron dysfunction. We argue that there is a positive feedback mechanism between (5) α-Syn aggregation and (3) autonomic dysfunction.

Figure 4

Courtesy of [23] (permission and license of usage were granted by publisher and supported by authors).(A) Schematic representation of the orientation of α-Syn in aqueous solution (left) and in the presence of lipopolysaccharides (LPS) micelle (right). Paramagnetic relaxation enhancement (PRE), using MnCl₂ as quenching agent, herein indicated only as “Mn”, was used by the authors to verify internalization of the N-terminal- and NAC regions of α-Syn into the LPS micelle. (B) Transmission electron microscopy (TEM) images showing morphologically distinct α-Syn fibrils at 1:1 LPS concentration at two different time points (t = 3 and 120 h). Scale = 200 nm. (C) Confocal microscopy images of fibrin networks formed from purified fibrinogen (with added Alexa 488 fluorophore) incubated with and without LPS from P. gingivalis, followed by addition of thrombin to create extensive fibrin(ogen) clots (unused raw data from [45].

Figure 5

An overview of the effects of the translocation of bacterial gingipain into the circulation: (1) immune evasion brought about by proteolytic degradation of antibodies, cytokines, and immune receptor CD14; (2) proteolytic degradation of transferrin (TFN) and haemoglobin (Hgb); (3) hypercoagulation caused directly by contact of platelets with gingipain proteases; and (4) amyloidogenesis, resulting not only from direct contact of neurons with gingipain proteases but also indirectly as a result of increased iron levels, which occur due to the degradation of iron-containing proteins.