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Exploiting Caenorhabditis elegans to discover human gut microbiota-mediated intervention strategies in protein conformational diseases
Daniel M. Czyż
2022, 17 (10):
2203-2204.
doi: 10.4103/1673-5374.335788
Age-dependent protein-conformational diseases (PCDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), or amyotrophic lateral sclerosis (ALS), are characterized by misfolding and aggregation of metastable proteins present within the proteome of the affected individual. Recent evidence supports the notion that bacteria and bacterial products may be affecting the stability of these culprit host proteins and therefore influence disease progression and perhaps even its onset. Although specific culprit proteins are associated with each disease (e.g., Aβ in AD, α-synuclein in PD, and TDP-43 in ALS), bacteria found to affect these diseases do not seem to differentiate between these specific proteins but likely affect host proteostasis in general, leading to misfolding of metastable proteins encoded within the proteome. The evidence that supports this hypothesis comes from studies where a single bacterial genus was linked to multiple PCDs. For example, a decrease in Prevotella spp. is linked to constipation, a condition that precedes PD motor symptoms by as much as 20 or more years (Savica et al., 2009; Zhu et al., 2014). Additionally, the abundance of Prevotella found in PD patients negatively correlates with the severity of the disease (Jin et al., 2019). Prevotella abundance was also lower in an AD mouse model (Shen et al., 2017) and ALS patients (Hertzberg et al., 2021), suggesting that this genus may provide protection against proteotoxicity. However, more research has to concentrate on Prevotella to understand its role in PCDs, as other studies have seen increased abundance in affected patients (Guo et al., 2021). Such discrepancy could be attributed to the large number of Prevotella species that may play diverse roles in disease pathogenesis, and since most studies looked at the genus level, the effect of individual species may provide additional clues. A recent study found two Prevotella species (i.e., disiens and corporis) that significantly suppressed polyglutamine protein aggregation in the Caenorhabditis elegans (C. elegans) model (Walker et al., 2021), suggesting that these specific species may enhance host proteostasis and protect the host against protein misfolding and aggregation. What is most promising is that the effect of Prevotella spp. on host proteostasis is observed across organisms, including worms, mice, and humans; therefore, less expensive, and manageable models, such as C. elegans, can be used as a discovery tool. The example of Prevotella and its potential role in the suppression of various PCDs demonstrates that bacteria affect host proteostasis and may be capable of influencing disease pathogenicity mediated by aggregation-prone proteins.
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