Editing Alpha-synuclein (section)

== Tissue expression ==

Alpha-synuclein is a [[synuclein]] [[protein]] primarily found in [[neural tissue]], making up as much as one percent of all proteins in the [[cytosol]] of [[brain cell]]s.<ref name="Iwai_1995">{{cite journal | vauthors = Iwai A, Masliah E, Yoshimoto M, Ge N, Flanagan L, de Silva HA, Kittel A, Saitoh T | title = The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system | journal = Neuron | volume = 14 | issue = 2 | pages = 467–475 | date = February 1995 | pmid = 7857654 | doi = 10.1016/0896-6273(95)90302-X | s2cid = 17941420 | doi-access = free }}</ref> It is expressed highly in neurons within the [[frontal cortex]], [[hippocampus]], [[striatum]], and [[olfactory bulb]],<ref name="Iwai_1995" /> but can also be found in the non-neuronal [[glial cells]].<ref>{{cite journal | vauthors = Filippini A, Gennarelli M, Russo I | title = α-Synuclein and Glia in Parkinson's Disease: A Beneficial or a Detrimental Duet for the Endo-Lysosomal System? | journal = Cellular and Molecular Neurobiology | volume = 39 | issue = 2 | pages = 161–168 | date = March 2019 | pmid = 30637614 | pmc = 11469870 | doi = 10.1007/s10571-019-00649-9 | s2cid = 58006790 }}</ref> In [[melanocyte]]s, SNCA protein expression may be regulated by [[microphthalmia-associated transcription factor]] (MITF).<ref name="Hoek_2008">{{cite journal | vauthors = Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E | title = Novel MITF targets identified using a two-step DNA microarray strategy | journal = Pigment Cell & Melanoma Research | volume = 21 | issue = 6 | pages = 665–676 | date = December 2008 | pmid = 19067971 | doi = 10.1111/j.1755-148X.2008.00505.x | s2cid = 24698373 | doi-access = free }}</ref>

It has been established that alpha-synuclein is extensively localized in the nucleus of mammalian brain neurons, suggesting a role of alpha-synuclein in the nucleus.<ref name="Yu_2007">{{cite journal | vauthors = Yu S, Li X, Liu G, Han J, Zhang C, Li Y, Xu S, Liu C, Gao Y, Yang H, Uéda K, Chan P | title = Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody | journal = Neuroscience | volume = 145 | issue = 2 | pages = 539–555 | date = March 2007 | pmid = 17275196 | doi = 10.1016/j.neuroscience.2006.12.028 | s2cid = 37294944 }}</ref> Synuclein is however found predominantly in the [[presynaptic]] termini, in both free or membrane-bound forms,<ref name="McLean_2000">{{cite journal | vauthors = McLean PJ, Kawamata H, Ribich S, Hyman BT | title = Membrane association and protein conformation of alpha-synuclein in intact neurons. Effect of Parkinson's disease-linked mutations | journal = The Journal of Biological Chemistry | volume = 275 | issue = 12 | pages = 8812–8816 | date = March 2000 | pmid = 10722726 | doi = 10.1074/jbc.275.12.8812 | doi-access = free }}</ref> with roughly 15% of synuclein being membrane-bound at any moment in neurons.<ref name="Lee_2002">{{cite journal | vauthors = Lee HJ, Choi C, Lee SJ | title = Membrane-bound alpha-synuclein has a high aggregation propensity and the ability to seed the aggregation of the cytosolic form | journal = The Journal of Biological Chemistry | volume = 277 | issue = 1 | pages = 671–678 | date = January 2002 | pmid = 11679584 | doi = 10.1074/jbc.M107045200 | s2cid = 10438997 | doi-access = free }}</ref>

It has also been shown that alpha-synuclein is localized in neuronal [[mitochondria]].<ref name="pmid 18817762">{{cite journal | vauthors = Zhang L, Zhang C, Zhu Y, Cai Q, Chan P, Uéda K, Yu S, Yang H | title = Semi-quantitative analysis of alpha-synuclein in subcellular pools of rat brain neurons: an immunogold electron microscopic study using a C-terminal specific monoclonal antibody | journal = Brain Research | volume = 1244 | pages = 40–52 | date = December 2008 | pmid = 18817762 | doi = 10.1016/j.brainres.2008.08.067 | s2cid = 1737088 }}</ref><ref name="pmid 19429081">{{cite journal | vauthors = Liu G, Zhang C, Yin J, Li X, Cheng F, Li Y, Yang H, Uéda K, Chan P, Yu S | title = alpha-Synuclein is differentially expressed in mitochondria from different rat brain regions and dose-dependently down-regulates complex I activity | journal = Neuroscience Letters | volume = 454 | issue = 3 | pages = 187–192 | date = May 2009 | pmid = 19429081 | doi = 10.1016/j.neulet.2009.02.056 | s2cid = 45120745 }}</ref> Alpha-synuclein is highly expressed in the mitochondria in [[olfactory bulb]], hippocampus, striatum and thalamus, where the cytosolic alpha-synuclein is also rich. However, the cerebral cortex and cerebellum are
two exceptions, which contain rich cytosolic alpha-synuclein but very low levels of mitochondrial alpha-synuclein. It has been shown that alpha-synuclein is localized in the inner membrane of mitochondria, and that the inhibitory effect of alpha-synuclein on [[Respiratory complex I|complex I]] activity of the mitochondrial respiratory chain is dose-dependent. Thus, it is suggested that alpha-synuclein in mitochondria is differentially expressed in different brain regions and the background levels of mitochondrial alpha-synuclein may be a potential factor affecting mitochondrial function and predisposing some neurons to degeneration.<ref name="pmid 19429081"/>

At least three isoforms of synuclein are produced through [[alternative splicing]].<ref name="Beyer_2006">{{cite journal | vauthors = Beyer K | title = Alpha-synuclein structure, posttranslational modification and alternative splicing as aggregation enhancers | journal = Acta Neuropathologica | volume = 112 | issue = 3 | pages = 237–251 | date = September 2006 | pmid = 16845533 | doi = 10.1007/s00401-006-0104-6 | s2cid = 1367846 }}</ref> The majority form of the protein, and the one most investigated, is the full-length protein of 140 amino acids. Other isoforms are alpha-synuclein-126, which lacks residues 41-54 due to loss of exon 3; and alpha-synuclein-112,<ref name="pmid 7802671">{{cite journal | vauthors = Uéda K, Saitoh T, Mori H | title = Tissue-dependent alternative splicing of mRNA for NACP, the precursor of non-A beta component of Alzheimer's disease amyloid | journal = Biochemical and Biophysical Research Communications | volume = 205 | issue = 2 | pages = 1366–1372 | date = December 1994 | pmid = 7802671 | doi = 10.1006/bbrc.1994.2816 }}</ref> which lacks residues 103-130 due to loss of exon 5.<ref name="Beyer_2006" />

=== 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" />