Exploring the "Multiple-Hit Hypothesis" of Neurodegenerative Disease: Bacterial Infection Comes Up to Bat

Abstract

Despite major strides in personalized genomics, it remains poorly understood why neurodegenerative diseases occur in only a fraction of individuals with a genetic predisposition and conversely, why individuals with no genetic risk of a disorder develop one. Chronic diseases like Alzheimer's, Parkinson's, and Multiple sclerosis are speculated to result from a combination of genetic and environmental factors, a concept commonly referred to as the "multiple hit hypothesis." A number of bacterial infections have been linked to increased risk of neurodegeneration, and in some cases, clearance of bacterial pathogens has been correlated with amelioration of central nervous system (CNS) deficits. Additionally, mutations in several genes known to contribute to CNS disorders like Parkinson's Disease have repeatedly been implicated in susceptibility to intracellular bacterial infection. Recent data has begun to demonstrate roles for these genes (PARK2, PINK1, and LRRK2) in modulating innate immune outcomes, suggesting that immune dysregulation may play an even more important role in neurodegeneration than previously appreciated. This review will broadly explore the connections between bacterial infection, immune dysregulation, and CNS disorders. Understanding this interplay and how bacterial pathogenesis contributes to the "multiple-hit hypothesis" of neurodegeneration will be crucial to develop therapeutics to effectively treat both neurodegeneration and infection.

Keywords: Alzheimer's; LRRK2; Mycobacterium tuberculosis; PINK1; Parkin (PARK2); Parkinson's; neuroinflammation; pathogenesis.

Figure 1

Schematic representation of the pathogens discussed in this review, the major organ system(s) they infect, and the primary innate immune cytokines they induce. Chlamydia pneumoniae is shown in its primary location (lung) but also in the CNS, where the bacterium has been repeatedly detected in association with AD (Balin et al., ; Arking et al., ; Gérard et al., 2006). Borrelia burgdorferi is a systemic infection, shown here in the CNS, where it too has been detected (Miklossy et al., 2004). Helicobacter pylori causes infection of the stomach and duodenum. Mycobacterium tuberculosis and Bordatella pertussis are mainly pathogens of the lung. The major resident oral pathogens, Treponema denitcola, Porphyromonas gingivalis, and Tannerella forsythia are shown in the mouth and gums. PT: pertussis toxin. Figure created with BioRender.

Figure 2

Schematic representation comparing and contrasting mitophagy and xenophagy of Mtb. During xenophagy of Mtb in macrophages (left), Mtb-containing vacuoles are decorated with ubiquitin via the E3 ligases Parkin (Watson et al., 2012) and Smurf1 (Franco et al., 2017). This recruits various selective autophagy adaptors (p62, NDP52, and NBR1) and, subsequently, LC3 and the autophagophore. Upon mitochondrial damage (right), the kinase PINK1 phosphorylates both Parkin and ubiquitin (Kondapalli et al., ; Kane et al., ; Koyano et al., ; Kazlauskaite and Muqit, 2015), allowing Parkin to ubiquitinate mitochondrial proteins. The E3 ligase SIAH1 also contributes to the ubiquitination of mitochondrial proteins (Szargel et al., 2016). As in xenophagy, this ubiquitination recruits selective autophagy adaptors (p62, OPTN, NDP52, and NBR1), LC3, and the autophagophore. Other ubiquitin-independent mechanisms, like cardiolipin-dependent mitophagy and receptor-mediated mitophagy, can also target damaged mitochondria to autophagy; in these pathways, exposed cardiolipin or outer membrane proteins directly recruit LC3 proteins or the closely related GAPARAP proteins. Both Mtb infection and mitochondrial damage activate the cytosolic DNA sensor cGAS (bottom), which elicits a type I IFN transcriptional program (Wassermann et al., ; Watson et al., ; West et al., ; Franco et al., 2017). Figure created with BioRender.