Editing Alpha-synuclein (section)

=== In the enteric nervous system (ENS) ===
First characterisations of aSyn aggregates in the ENS of PD patients has been performed on autopsied specimens in the late 1980s.<ref name="Schaeffer_2020">{{cite journal | vauthors = Schaeffer E, Kluge A, Böttner M, Zunke F, Cossais F, Berg D, Arnold P | title = Alpha Synuclein Connects the Gut-Brain Axis in Parkinson's Disease Patients - A View on Clinical Aspects, Cellular Pathology and Analytical Methodology | journal = Frontiers in Cell and Developmental Biology | volume = 8 | pages = 573696 | date = 2020 | pmid = 33015066 | pmc = 7509446 | doi = 10.3389/fcell.2020.573696 | doi-access = free }}</ref> It is yet unknown if the microbiome changes associated with PD are consequential to the illness process or main pathophysiology, or both.<ref>{{cite journal | vauthors = Anis E, Xie A, Brundin L, Brundin P | title = Digesting recent findings: gut alpha-synuclein, microbiome changes in Parkinson's disease | journal = Trends in Endocrinology and Metabolism: TEM | volume = 33 | issue = 2 | pages = 147–157 | date = February 2022 | pmid = 34949514 | doi = 10.1016/j.tem.2021.11.005 | language = English | s2cid = 245351514 }}</ref>

Individuals diagnosed with various synucleinopathies often display constipation and other GI dysfunctions years prior to the onset of movement dysfunction.<ref name="Sampson_2020">{{cite journal | vauthors = 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 | veditors = Chiu IM, Garrett WS, Desjardins M | title = A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice | journal = eLife | volume = 9 | pages = e53111 | date = February 2020 | pmid = 32043464 | pmc = 7012599 | doi = 10.7554/eLife.53111 | doi-access = free }}</ref>

Alpha synuclein potentially connects the gut-brain axis in [[Parkinson's disease]] patients. Common inherited Parkinson disease is associated with mutations in the alpha-synuclein (SNCA) gene. In the process of seeded nucleation, alpha-synuclein acquires a cross-sheet structure similar to other amyloids.<ref name="Schaeffer_2020" />

The ''[[Enterobacteriaceae]]'', which are quite common in the human gut, can create [[curli]], which are functional amyloid proteins. The unfolded [[amyloid]] CsgA, which is secreted by bacteria and later aggregates extracellularly to create biofilms, mediates adherence to epithelial cells, and aids in bacteriophage defense, forms the curli fibers. Oral injection of curli-producing bacteria can also boost formation and aggregation of the amyloid protein Syn in old rats and [[nematode]]s. Host inflammation responses in the intestinal tract and periphery are modulated by curli exposure. Studies in biochemistry show that endogenous, bacterial chaperones of curli are capable of briefly interacting with Syn and controlling its aggregation.<ref name="Sampson_2020" />

The clinical and pathological findings support the hypothesis that aSyn disease in PD occurs via a gut-brain pathway. For early diagnosis and early management in the phase of creation and propagation of aSyn, it is therefore of utmost importance to identify pathogenic aSyn in the digestive system, for example, by gastrointestinal tract (GIT) biopsies.<ref name="Schaeffer_2020" />

According to a growing body of research, intestinal dysbiosis may be a major factor in the development of Parkinson's disease by encouraging intestinal permeability, gastrointestinal inflammation, and the aggregation and spread of asyn.<ref name="Schaeffer_2020" />

Not just the CNS but other peripheral tissues, such as the GIT, have physiological aSyn expression as well as its phosphorylated variants.<ref>{{cite journal | vauthors = Barrenschee M, Zorenkov D, Böttner M, Lange C, Cossais F, Scharf AB, Deuschl G, Schneider SA, Ellrichmann M, Fritscher-Ravens A, Wedel T | title = Distinct pattern of enteric phospho-alpha-synuclein aggregates and gene expression profiles in patients with Parkinson's disease | journal = Acta Neuropathologica Communications | volume = 5 | issue = 1 | pages = 1 | date = January 2017 | pmid = 28057070 | pmc = 5217296 | doi = 10.1186/s40478-016-0408-2 | doi-access = free }}</ref> As suggested by Borghammer and Van Den Berge (2019), one approach is to recognise the possibility of PD subtypes with various aSyn propagation methods, including either a peripheral nervous system (PNS)-first or a CNS-first route.<ref>{{cite journal | vauthors = Borghammer P, Van Den Berge N | title = Brain-First versus Gut-First Parkinson's Disease: A Hypothesis | journal = Journal of Parkinson's Disease | volume = 9 | issue = s2 | pages = S281–S295 | date = 2019-10-30 | pmid = 31498132 | pmc = 6839496 | doi = 10.3233/jpd-191721 }}</ref>

While the GI tract has been linked to other neurological disorders such [[Autism spectrum|autism spectrum disorder]], [[Depression (mood)|depression]], [[anxiety]], and [[Alzheimer's disease]], protein aggregation and/or inflammation in the gut represent a new topic of investigation in [[Synucleinopathy|synucleinopathies]].<ref name="Sampson_2020" />