Abstract
Misfolded and abnormal β-sheets forms of wild-type proteins, such as cellular prion protein (PrPC) and amyloid beta (Aβ), are believed to be the vectors of neurodegenerative diseases, prion and Alzheimer’s disease (AD), respectively. Increasing evidence highlights the “prion-like” seeding of protein aggregates as a mechanism for pathological spread in AD, tauopathy, as well as in other neurodegenerative diseases, such as Parkinson’s. Mutations in both PrPC and Aβ precursor protein (APP), have been associated with the pathogenesis of these fatal disorders with clear evidence for their pathogenic significance. In addition, a critical role for the gut microbiota is emerging; indeed, as a consequence of gut–brain axis alterations, the gut microbiota has been involved in the regulation of Aβ production in AD and, through the microglial inflammation, in the amyloid fibril formation, in prion diseases. Here, we aim to review the role of microbiome (“the other human genome”) alterations in AD and prion disease pathogenesis.
Highlights
Prion diseases, similar to Alzheimer’s and Parkinson’s diseases, are based on the aggregation of abnormal protein assemblies which could result in a cascade of neurodegenerative pathways
The vicious circle of spread, seed, and accumulation of misfolded protein aggregates within the central nervous system is restricted to prion protein PrP, but has been reported for other proteins, such as Aβ, α-synuclein, and tau, that are able to form amyloidogenic aggregates which spread through the brain and cause distinct neurodegenerative diseases [3,45]
Mutations in the genes codifying for these proteins have been associated with the pathogenesis of prion diseases and Alzheimer’s disease (AD), and have been described to alter protein trafficking, processing, dynamic stability, folding, and ability to aggregate inside the cells [5,6]
Summary
Similar to Alzheimer’s and Parkinson’s diseases, are based on the aggregation of abnormal protein assemblies which could result in a cascade of neurodegenerative pathways. It has been hypothesized that PRNP mutations are able to lower the energy barrier for the conversion of the normal cellular PrP into the scrapie, pathological PrPSc isoform [2] The latter, according to the recently proposed concept of “propagating misfolding”, can modulate the misfolding of the normal protein into the misfolded amyloidogenic isoform [3]. The infective prion disease pathogenesis is based on protein misfolding triggered by prions entering the gut [7] where microbiomal factors (e.g., Curli proteins) can act as a template for amyloid fibril formation though a cross-seeding event [8]. This suggests that the gut microbiota may play a. We will review the current knowledge regarding the role of the gut microbiome in these two neurodegenerative disorders
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