Our understanding of dysfunction of the gastrointestinal system in patients with Parkinson's disease has increased substantially in the past decade. The entire gastrointestinal tract is affected in these patients, causing complications that range from oral issues, including drooling and swallowing problems, to delays in gastric emptying and constipation. Additionally, small intestinal bacterial overgrowth and Helicobacter pylori infection affect motor fluctuations by interfering with the absorption of antiparkinsonian drugs. The multifaceted role of the gastrointestinal system in Parkinson's disease necessitates a specific and detailed assessment and treatment plan. The presence of pervasive α-synuclein deposition in the gastrointestinal tract strongly implicates this system in the pathogenesis of Parkinson's disease. Future studies elucidating the role of the gastrointestinal tract in the pathological progression of Parkinson's disease might hold potential for early disease detection and development of neuroprotective approaches.
The clinical and pathological differences between synucleinopathies such as Parkinson's disease and multiple system atrophy have been postulated to stem from unique strains of α-synuclein aggregates, akin to what occurs in prion diseases. Here, we demonstrate that inoculation of transgenic mice with different strains of recombinant or brain-derived α-synuclein aggregates produces clinically and pathologically distinct diseases. Strain-specific differences were observed in the signs of neurological illness, time to disease onset, morphology of cerebral α-synuclein deposits, and the conformational properties of the induced aggregates. Moreover, different strains targeted distinct cellular populations and cell types within the brain, recapitulating the selective targeting observed between human synucleinopathies. Strain-specific clinical, pathological, and biochemical differences were faithfully maintained upon serial passaging, implying that αsynuclein propagates via prion-like conformational templating. Thus, pathogenic α-synuclein exhibits key hallmarks of prion strains, providing evidence that disease heterogeneity among the synucleinopathies is caused by distinct α-synuclein strains.Parkinson's disease (PD) and related diseases, including dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), are progressive neurodegenerative disorders. The brains of PD, DLB, and MSA patients contain intracellular inclusions composed of aggregated α-synuclein (α-syn). Thus, these diseases are commonly referred to as αsynucleinopathies, or simply synucleinopathies 1 . α-Syn is a 140-amino acid cytoplasmic protein that is found within presynaptic nerve terminals and is involved in the assembly of SNARE complexes 2 . In disease, α-syn polymerizes into insoluble β-sheet-rich protein aggregates that become phosphorylated at residue Ser129 and deposit within the central nervous system 3,4 . α-Syn is believed to play a central pathogenic role in the synucleinopathies since mutation of the gene encoding α-syn causes early-onset PD 5 .There is mounting evidence that α-syn becomes "prion-like" during disease, leading to a progressive cell-to-cell spreading of protein aggregates within the brain 6 . Prions are selfpropagating protein aggregates that cause neurodegenerative disorders such as Creutzfeldt-Jakob disease in humans and scrapie in sheep. Prion replication and spreading is thought to occur via a template-directed refolding mechanism, in which aggregated prion protein (PrP) catalyzes the conformational conversion of properly-folded PrP into additional copies of the misfolded form 7 . Similar to the experimental transmission of prion disease, injection of mice with pre-formed α-syn aggregates induces the aggregation and deposition of α-syn within the brain and, in some instances, accelerates the onset of neurological illness [8][9][10][11][12][13] . The prionlike behavior of α-syn aggregates provides a potential molecular explanation for the progressive nature of PD and related synucleinopathies.The synucleinopathies ar...
Parkinson’s disease (PD) is a progressive neurodegenerative disorder typified by the presence of intraneuronal inclusions containing aggregated alpha synuclein (αsyn). The progression of parkinsonian pathology and clinical phenotype has been broadly demonstrated to follow a specific pattern, most notably described by Braak and colleagues. In more recent times it has been hypothesized that αsyn itself may be a critical factor in mediating transmission of disease pathology from one brain area to another. Here we investigate the growing body of evidence demonstrating the ability of αsyn to spread transcellularly and induce pathological aggregation affecting neurons by permissive templating and provide a critical analysis of some irregularities in the hypothesis that the progression of PD pathology may be mediated by such a prion-like process. Finally we discuss some key questions that remain unanswered which are vital to determining the potential contribution of a prion-like process to the pathogenesis of PD.
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