Can infections trigger alpha-synucleinopathies?

Abstract

As synucleinopathies, Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases that involve the spread of pathogenic alpha-synuclein (αSyn) throughout the brain. Recent studies have suggested a role for αSyn as an antimicrobial peptide in response to PD- and MSA-related infections of peripheral tissues, including those in the respiratory, gastrointestinal, and urogenital systems. In this chapter, we examine epidemiological and experimental evidence for a role of peripheral microbial infections in triggering alpha-synucleinopathies. We propose a model of how infectious triggers, in conjunction with inflammatory, environmental, and genetic facilitators, may result in transfer of pathogenic αSyn strains from the periphery to the brain, where they propagate and spread. Finally, we discuss future research challenges and programs necessary to clarify the role of infections as triggers of PD and MSA and, ultimately, to prevent the onset of these diseases by infectious triggers.

Keywords: Alpha-synuclein; Antimicrobial peptides; Bacteria; Facilitators; Fungi; Infections; Multiple system atrophy; Parkinson's disease; Triggers; Viruses.

Fig. 1

Potential routes of entry for infectious triggers of alpha-synucleinopathies. (A) Infectious triggers of Parkinson’s disease (PD) may infect respiratory system tissues, including the nasal passage, innervated by the olfactory nerves of the olfactory bulbs, and the lungs, innervated by the vagus nerve (left). In the presence of facilitators, alpha-synuclein (αSyn) deposition occurs in neurons before propagating interneuronally along these nerves to the olfactory bulbs and brainstem before spreading through the brain (right). (B) Infectious triggers of PD may also infect gastrointestinal system tissues, including the liver and intestines, which are innervated by the vagus nerve (left). In the presence of facilitators, αSyn propagates interneuronally along the vagus nerve to the brainstem before spreading through the brain (right). (C) Infectious triggers of multiple system atrophy (MSA) may enter the body and infect tissues of the urogenital system or distal colon (left). In the presence of facilitators, αSyn deposition occurs in Schwann cells and oligodendrocytes. αSyn transfers between these cells and neurons to the brainstem, from which alpha-synucleinopathy spreads in the brain, including the cerebellum (right).

Fig. 2

Model of peripheral infections as triggers of alpha-synucleinopathies in the brain. (A) Tissues of the respiratory, gastrointestinal, or urogenital systems are infected by microbial triggers including viruses, fungi, or bacteria. (B) Cells of these tissues, including neurons in PD and oligodendrocytes in MSA, experience an inflammatory response to the infection and produce alpha-synuclein (αSyn) as an antimicrobial peptide. (C) A second hit of environmental, genetic, or inflammatory facilitators leads to aggregation of potentially seeding-competent assemblies of alpha-synuclein, which form Lewy bodies and neurites. (D) αSyn and brain penetrant infections are transferred retrogradely along the nervous tissues that innervate the infected peripheral organs, ultimately reaching the brain. (E) Pathogenic αSyn seeds lead to neuroinflammation and propagation of alpha-synucleinopathy throughout the brain over decades.