Dysbiosis of the gut microbiota and its effect on α-synuclein and prion protein misfolding: consequences for neurodegeneration

Abstract

Abnormal behavior of α-synuclein and prion proteins is the hallmark of Parkinson's disease (PD) and prion illnesses, respectively, being complex neurological disorders. A primary cause of protein aggregation, brain injury, and cognitive loss in prion illnesses is the misfolding of normal cellular prion proteins (PrP^C) into an infectious form (PrP^Sc). Aggregation of α-synuclein causes disruptions in cellular processes in Parkinson's disease (PD), leading to loss of dopamine-producing neurons and motor symptoms. Alteration in the composition or activity of gut microbes may weaken the intestinal barrier and make it possible for prions to go from the gut to the brain. The gut-brain axis is linked to neuroinflammation; the metabolites produced by the gut microbiota affect the aggregation of α-synuclein, regulate inflammation and immunological responses, and may influence the course of the disease and neurotoxicity of proteins, even if their primary targets are distinct proteins. This thorough analysis explores the complex interactions that exist between the gut microbiota and neurodegenerative illnesses, particularly Parkinson's disease (PD) and prion disorders. The involvement of the gut microbiota, a complex collection of bacteria, archaea, fungi, viruses etc., in various neurological illnesses is becoming increasingly recognized. The gut microbiome influences neuroinflammation, neurotransmitter synthesis, mitochondrial function, and intestinal barrier integrity through the gut-brain axis, which contributes to the development and progression of disease. The review delves into the molecular mechanisms that underlie these relationships, emphasizing the effects of microbial metabolites such as bacterial lipopolysaccharides (LPS), and short-chain fatty acids (SCFAs) in regulating brain functioning. Additionally, it looks at how environmental influences and dietary decisions affect the gut microbiome and whether they could be risk factors for neurodegenerative illnesses. This study concludes by highlighting the critical role that the gut microbiota plays in the development of Parkinson's disease (PD) and prion disease. It also provides a promising direction for future research and possible treatment approaches. People afflicted by these difficult ailments may find hope in new preventive and therapeutic approaches if the role of the gut microbiota in these diseases is better understood.

Keywords: Parkinson’s disease; and neurodegeneration; gut microbiota; neuro-inflammation; prion disease; prion protein; short-chain fatty acids; α-synuclein.

Figure 1

PrP^C Structural Domains: Navigating Prion Protein's Complexity. The prion protein (PrP^C) is characterized by distinct domains – a disordered N-terminal with a pivotal charged region for endocytosis, octapeptide repeats binding metal cations and a hydrophobic tract. The C-terminal boasts α-helices and β-strands, hosting post-translational modifications: N-glycans enhance function, a disulfide bridge bolsters structure and a C-terminal GPI anchor affixes PrP^C to the plasma membrane. This intricate architecture defines PrP^C's multifunctional nature.

Figure 2

A schematic depiction has been formulated to elucidate the proposed mechanisms underlying the conversion of PrP^C into PrP^Sc and the subsequent process of aggregation. (A) Template assistance Model, (B) Nucleation-Polymerization Model. The interaction between PrP^Sc and PrP^C is depicted in the Template Assistance Model (A), where PrPSc functions as a template and causes conformational change in PrP^C. The spread of prion disease depends on this template-assisted conversion, which triggers aggregation later. On the other hand, a multi-step nucleation and polymerization process is depicted in the Nucleation-Polymerization Model (B). The first step is the formation of a nucleus, or seed, which catalyzes the transformation of PrP^C molecules into PrP^Sc and then polymerization. To convert PrP^C to PrP^Sc, both models highlight the importance of templating and sequential conformational changes, with subsequent aggregation events contributing to the progression of prion diseases. This visual representation aids in elucidating the intricate molecular events central to prion pathology. Created with BioRender.com.

Figure 3

Demonstrating the Scientific Impact of Transitional Entities During Prion Aggregation: Analyzing Molecular Complexity. This diagram that illustrates the phases of prion aggregation emphasizes the pathogenicity linked to monomeric PrP^Sc, small oligomeric assemblies, and PrP pre-fibrillar structures-all of which are thought to act as triggers for prion-induced neuronal death. Created with BioRender.com.

Figure 4

Diagram illustrating the structure of alpha-synuclein. Labeled amino acid residues include known sites of mutations and define the N-terminus, NAC region, and C-terminus. Three different domains can be differentiated from the 140 amino acid protein. The amino acid residues impacted by the primary alpha-synuclein gene mutations (A18T, A30P, A29S, E46K, H50Q, G51D, and A53T/E/V) linked to autosomal dominant Parkinson's disease are found in the N-terminal amphipathic domain. Membrane binding is carried out by the N-terminal region, which has a predisposition for helical folding. Aggregation is encouraged by the hydrophobic non-amyloid β-component of plaque (NAC) domain. The primary phosphorylation site is located at Ser129 in the acidic tail that the C-terminal domain produces and α-synuclein aggregation is modulated by the C-terminal domain.

Figure 5

Common mechanisms serve as the groundwork for Parkinson’s disease pathogenesis. Inside nerve cells, the protein α-synuclein misfolds and creates poisonous clumps called Lewy bodies. The apparent motor symptoms of the illness might be driven by these aggregates, which can disrupt neuronal activity, impair cells, and ultimately perish dopamine-producing neurons. Created with BioRender.com.

Figure 6

Mapping the Progression: Sequential Buildup and Transmission of α-Synuclein from Enteric Nervous System (ENS) to the Central Nervous System (CNS). Environmental factors, including microorganisms and the gastrointestinal microbiota (GM), induce a progressive buildup of α-synuclein within the extracellular matrix. Through this process, a pathological cascade that causes oxidative stress and mucosal inflammation is started, which eventually leads to the formation of α-synuclein aggregates. The vagal nerve is the proposed conduit. Pathological transmission of α-synuclein proceeds via the brainstem, midbrain, and basal forebrain, ultimately reaching cortical areas. The dynamics of α-synuclein pathogenesis from the ENS to the CNS are described in this visual representation. Created with BioRender.com.