Sampson TR, Challis C, Jain N, Moiseyenko A, Ladinsky MS, Shastri GG, Thron T, Needham BD, Horvath I, Debelius JW, Janssen S, Knight R, Wittung-Stafshede P, Gradinaru V, Chapman M, Mazmanian SK. A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice. Elife. 2020 Feb 11;9 PubMed.
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University of Louisville School of Medicine
The great majority of cases of neurodegenerative disease are not caused by genes. This new paper from the laboratory of S. Mazmanian provides further evidence that amyloid proteins made by gut bacteria play key roles in the initiation of neurodegeneration. In 2016 this group demonstrated that germ-free, α-synuclein-overexpressing, Parkinson model mice were relatively protected from the behavioral and structural features of the disease (Sampson et al., 2016). In this new paper they convincingly demonstrate that the bacterial amyloid protein curli is a key instigator of protein aggregation and neuroinflammation in the gut and brain in this model system. Furthermore, injection of curli into the intestinal wall increased α-synuclein fibril deposition in the midbrain. In addition, oral treatment of the mice with the polyphenol epigallocatechin gallate (EGCG) decreased production of curli, improving motor deficits.
I proposed a key role for bacterial amyloid in the triggering of prion-like misfolding of brain proteins and priming of the innate immune system in 2015 (Friedland 2015). This was supported by our studies in aged rats and nematodes (Chen et al, 2016; Friedland and Chapman, 2017; and Oct 2016 news). Now, Sampson et al. reinforce interest in the involvement of microbial amyloids in neurodegeneration and demonstrate the exciting promise for neurodegenerative disease therapies targeting the intestinal microbiota and their products directly, without the need for therapeutic or preventive agents to enter the brain.
References:
Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell. 2016 Dec 1;167(6):1469-1480.e12. PubMed.
Friedland RP. Mechanisms of molecular mimicry involving the microbiota in neurodegeneration. J Alzheimers Dis. 2015;45(2):349-62. PubMed.
Chen SG, Stribinskis V, Rane MJ, Demuth DR, Gozal E, Roberts AM, Jagadapillai R, Liu R, Choe K, Shivakumar B, Son F, Jin S, Kerber R, Adame A, Masliah E, Friedland RP. Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans. Sci Rep. 2016 Oct 6;6:34477. PubMed.
Friedland RP, Chapman MR. The role of microbial amyloid in neurodegeneration. PLoS Pathog. 2017 Dec;13(12):e1006654. Epub 2017 Dec 21 PubMed.
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