Alpha-synuclein
α-Synuclein eller alpha-synuclein er et protein, der findes i den menneskelige hjerne primært i præsynaptiske terminaler. α-Synuclein kan også være til stede i små mængder i hjertet, musklerne og andre væv.
α-Synuclein har specielt tiltrukket sig opmærksomheden, da det er stærkt impliceret i udviklingen af adskillige neurodegenerative sygdomme, nu kollektivt kendt som synukleinopatier: Parkinsons sygdom og relaterede tilstande, bl.a. demens med lewy legemer (DLB) og multiple system atrophy (MSA). Ved disse sygdomme medfører ophobningen af aggregater i neuronerne en ubalance, som kan resultere i nedsatte cellulære funktioner og celledød.[1][2]
Den nøjagtige funktion af α-synuclein er ikke kendt, men det er blevet foreslået at være involveret i synaptisk funktion og plasticitet, såvel som i reguleringen af dopaminfrigivelse, som er en kritisk neurotransmitter i reguleringen af bevægelse.
Biokemi
Alpha-synuclein er opbygget af 140 aminosyrer og er i mennesker kodet af SNCA-genet.
Aggregering af α-synuclein fremstår som den mest sandsynlige molekylære proces, der starter den neurodegenerative proces, der leder til synukleinopati. Aggregering fremstår som en følge af den manglende indre struktur, hvor den store molekylære fleksibilitet faciliterer mange kompleksdannelser. Aggregeringen sker ikke alene mellem α-synuclein molekyler, men inddrager andre molekyler i opbygningen af molekylkomplekser, fibriller og makrostrukturer der hæmmer og afsporer cellernes normale funktioner. Aggregeringen bidrager således til fibrillering af amyloid-b og tau-proteinet, to nøgleproteiner i Alzheimers sygdom, hvilket antyder en central rolle for α-synuclein i neurodegeneration.[3]
Se også
- Intrinsikt uordnet protein
Henvisninger
- ^ Gådefuld sygdom er i eksplosiv vækst. Ugeskrift for Læger 2023
- ^ The Effect of Aggregated Alpha Synuclein on Synaptic and Axonal Proteins in Parkinson’s Disease—A Systematic Review. Biomolecules 2022
- ^ α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nature Medicine 2017
Medier brugt på denne side
Forfatter/Opretter: Mark R Cookson, Licens: CC BY 2.0
Events in α-synuclein toxicity. The central panel shows the major pathway for protein aggregation. Monomeric α-synuclein is natively unfolded in solution but can also bind to membranes in an α-helical form. It seems likely that these two species exist in equilibrium within the cell, although this is unproven. From in vitro work, it is clear that unfolded monomer can aggregate first into small oligomeric species that can be stabilized by β-sheet-like interactions and then into higher molecular weight insoluble fibrils. In a cellular context, there is some evidence that the presence of lipids can promote oligomer formation: α-synuclein can also form annular, pore-like structures that interact with membranes. The deposition of α-synuclein into pathological structures such as Lewy bodies is probably a late event that occurs in some neurons. On the left hand side are some of the known modifiers of this process. Electrical activity in neurons changes the association of α-synuclein with vesicles and may also stimulate polo-like kinase 2 (PLK2), which has been shown to phosphorylate α-synuclein at Ser129. Other kinases have also been proposed to be involved. As well as phosphorylation, truncation through proteases such as calpains, and nitration, probably through nitric oxide (NO) or other reactive nitrogen species that are present during inflammation, all modify synuclein such that it has a higher tendency to aggregate. The addition of ubiquitin (shown as a black spot) to Lewy bodies is probably a secondary process to deposition. On the right are some of the proposed cellular targets for α-synuclein mediated toxicity, which include (from top to bottom) ER-golgi transport, synaptic vesicles, mitochondria and lysosomes and other proteolytic machinery. In each of these cases, it is proposed that α-synuclein has detrimental effects, listed below each arrow, although at this time it is not clear if any of these are either necessary or sufficient for toxicity in neurons. Cookson Molecular Neurodegeneration 2009 4:9 doi:10.1186/1750-1326-4-9
Forfatter/Opretter: Marvin 101, Licens: CC BY-SA 3.0
Immunohistochemistry for alpha-synuclein showing positive staining (brown) of an intraneural Lewy-body in the Substantia nigra in Parkinson's disease.