Why you should always go with your gut feeling: The role of functional amyloids in Parkinson’s disease

TY - BOOK

T1 - Why you should always go with your gut feeling

T2 - The role of functional amyloids in Parkinson’s disease

AU - Christensen, Line

PY - 2020

Y1 - 2020

N2 - Most functional amyloid proteins are evolutionarily optimized to assemble into a characteristic cross-beta structure. Formation of functional amyloids are under stringent control to avoid the cytotoxicity that is associated with some on-pathway oligomers. Functional amyloids are found in all domains of life (Bacteria, Archaea and Eukarya) and serve different roles, e.g. in bacterial biofilm stabilization and formation. In this thesis, we identify a second – and presumably more widespread – major sheathprotein (MspA) from the archaeal methanogen Methanospirillum hungatei. MspA forms hoop structures that make up the tubular and stable sheaths in which the individual bacteria live and divide. The thesis also takes a closer look at the functional amyloid protein FapC for which we investigate the importance of its three imperfect repeats – which are believed to be the main drivers of amyloid formation – in terms of providing stability to the resulting, mature fibrils. We find that removing two out of three repeats leads to a marked decrease in stability and in the number of residues that drive amyloid formation. Secondly, FapC and its repeat-free counterpart, FapC deltaR123, are investigated for their ability to interact with a-synuclein (a-SN), which is largely implicated in Parkinson’s disease (PD). Whereas we did not see any immediate effect of FapC, FapC deltaR123 – which display very irregular fibrillation – could delay a-SN fibrillation up to 4-fold. This inhibition was dependent on the ability of FapC deltaR123 to form disulfide-bonded higher-order species and mixed oligomers with a-SN. We also look for novel functional amyloid proteins in stool samples from both wild-type and transgenic PD rats because increasing evidence suggests that PD might originate in the gut and because cross-seeding between amyloid proteins might be a disease mechanism. Despite their young age (3 months), we observe a change in microbiome composition between wild-type and PD rats. In addition, we identifytwo proteins which share many features with other functional amyloid proteins. They, however, did not affect a-SN fibrillation under the in vitro condition applied.In conclusion, this thesis provides insight into the identification and characterization of novel functional amyloid proteins. In addition, it discusses and investigates the likelihood of gut microbiome bacteria being involved in diseases like PD – possibly through formation of amyloid-containing bacterial biofilms – by investigating interactions between a-SN and various gut-relevant amyloidogenic proteins.

AB - Most functional amyloid proteins are evolutionarily optimized to assemble into a characteristic cross-beta structure. Formation of functional amyloids are under stringent control to avoid the cytotoxicity that is associated with some on-pathway oligomers. Functional amyloids are found in all domains of life (Bacteria, Archaea and Eukarya) and serve different roles, e.g. in bacterial biofilm stabilization and formation. In this thesis, we identify a second – and presumably more widespread – major sheathprotein (MspA) from the archaeal methanogen Methanospirillum hungatei. MspA forms hoop structures that make up the tubular and stable sheaths in which the individual bacteria live and divide. The thesis also takes a closer look at the functional amyloid protein FapC for which we investigate the importance of its three imperfect repeats – which are believed to be the main drivers of amyloid formation – in terms of providing stability to the resulting, mature fibrils. We find that removing two out of three repeats leads to a marked decrease in stability and in the number of residues that drive amyloid formation. Secondly, FapC and its repeat-free counterpart, FapC deltaR123, are investigated for their ability to interact with a-synuclein (a-SN), which is largely implicated in Parkinson’s disease (PD). Whereas we did not see any immediate effect of FapC, FapC deltaR123 – which display very irregular fibrillation – could delay a-SN fibrillation up to 4-fold. This inhibition was dependent on the ability of FapC deltaR123 to form disulfide-bonded higher-order species and mixed oligomers with a-SN. We also look for novel functional amyloid proteins in stool samples from both wild-type and transgenic PD rats because increasing evidence suggests that PD might originate in the gut and because cross-seeding between amyloid proteins might be a disease mechanism. Despite their young age (3 months), we observe a change in microbiome composition between wild-type and PD rats. In addition, we identifytwo proteins which share many features with other functional amyloid proteins. They, however, did not affect a-SN fibrillation under the in vitro condition applied.In conclusion, this thesis provides insight into the identification and characterization of novel functional amyloid proteins. In addition, it discusses and investigates the likelihood of gut microbiome bacteria being involved in diseases like PD – possibly through formation of amyloid-containing bacterial biofilms – by investigating interactions between a-SN and various gut-relevant amyloidogenic proteins.

KW - Amyloid

KW - Parkinson's disease

KW - Cross-seeding

KW - Functional amyloid

KW - Microbiome

M3 - Ph.d.-afhandling

BT - Why you should always go with your gut feeling

PB - Århus Universitet

ER -