Intrinsically Disordered Proteins and Proteins with Intrinsically Disordered Regions in Neurodegenerative Diseases

Overview

Journal Biophys Rev

Publisher Springer

Specialty Biophysics

Date 2022 Jul 6

PMID 35791387

Authors

Orkid Coskuner-Weber

Ozan Mirzanli

Vladimir N Uversky

Affiliations

Soon will be listed here.

Abstract

Many different intrinsically disordered proteins and proteins with intrinsically disordered regions are associated with neurodegenerative diseases. These types of proteins including amyloid-β, tau, α-synuclein, CHCHD2, CHCHD10, and G-protein coupled receptors are increasingly becoming evaluated as potential drug targets in the pharmaceutical-based treatment approaches. Here, we focus on the neurobiology of this class of proteins, which lie at the center of numerous neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, Huntington's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Charcot-Marie-Tooth diseases, spinal muscular atrophy, and mitochondrial myopathy. Furthermore, we discuss the current treatment design strategies involving intrinsically disordered proteins and proteins with intrinsically disordered regions in neurodegenerative diseases. In addition, we emphasize that although the G-protein coupled receptors are traditionally investigated using structural biology-based models and approaches, current studies show that these receptors are proteins with intrinsically disordered regions and therefore they require new ways for their analysis.

Citing Articles

Mechanisms of ubiquitin-independent proteasomal degradation and their roles in age-related neurodegenerative disease.

Church T, Margolis S Front Cell Dev Biol. 2025; 12:1531797.

PMID: 39990094 PMC: 11842346. DOI: 10.3389/fcell.2024.1531797.

Global analysis of endogenous protein disorder in cells.

Zhang S, Owyong T, Sanislav O, Englmaier L, Sui X, Wang G Nat Methods. 2024; 22(1):124-134.

PMID: 39587358 DOI: 10.1038/s41592-024-02507-z.

Gene and transcript expression patterns, coupled with isoform switching and long non-coding RNA dynamics in adipose tissue, underlie the longevity of Ames dwarf mice.

Cano-Besquet S, Park M, Berkley N, Wong M, Ashiqueali S, Noureddine S Geroscience. 2024; .

PMID: 39405012 DOI: 10.1007/s11357-024-01383-x.

Osmotic stress induces formation of both liquid condensates and amyloids by a yeast prion domain.

Grizel A, Gorsheneva N, Stevenson J, Pflaum J, Wilfling F, Rubel A J Biol Chem. 2024; 300(10):107766.

PMID: 39276934 PMC: 11736011. DOI: 10.1016/j.jbc.2024.107766.

VUS next in rare diseases? Deciphering genetic determinants of biomolecular condensation.

Heredia-Torrejon M, Montanez R, Gonzalez-Meneses A, Carcavilla A, Medina M, Lechuga-Sancho A Orphanet J Rare Dis. 2024; 19(1):327.

PMID: 39243101 PMC: 11380411. DOI: 10.1186/s13023-024-03307-6.

References

Poon C, Wang Y, Fung M, Zhang C, Lim L . Rodent Models of Amyloid-Beta Feature of Alzheimer's Disease: Development and Potential Treatment Implications. Aging Dis. 2020; 11(5):1235-1259. PMC: 7505263. DOI: 10.14336/AD.2019.1026. View

Oates M, Romero P, Ishida T, Ghalwash M, Mizianty M, Xue B . D²P²: database of disordered protein predictions. Nucleic Acids Res. 2012; 41(Database issue):D508-16. PMC: 3531159. DOI: 10.1093/nar/gks1226. View

Oldfield C, Meng J, Yang J, Yang M, Uversky V, Dunker A . Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners. BMC Genomics. 2008; 9 Suppl 1:S1. PMC: 2386051. DOI: 10.1186/1471-2164-9-S1-S1. View

Bartfai T, Wang M . Positive allosteric modulators to peptide GPCRs: a promising class of drugs. Acta Pharmacol Sin. 2013; 34(7):880-5. PMC: 4002610. DOI: 10.1038/aps.2013.20. View

Gaier E, Eipper B, Mains R . Copper signaling in the mammalian nervous system: synaptic effects. J Neurosci Res. 2012; 91(1):2-19. PMC: 3926505. DOI: 10.1002/jnr.23143. View

Kosmidis S, Polyzos A, Harvey L, Youssef M, Denny C, Dranovsky A . RbAp48 Protein Is a Critical Component of GPR158/OCN Signaling and Ameliorates Age-Related Memory Loss. Cell Rep. 2018; 25(4):959-973.e6. PMC: 7725275. DOI: 10.1016/j.celrep.2018.09.077. View

Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J . Amyloid-beta: a crucial factor in Alzheimer's disease. Med Princ Pract. 2014; 24(1):1-10. PMC: 5588216. DOI: 10.1159/000369101. View

Fonin A, Darling A, Kuznetsova I, Turoverov K, Uversky V . Multi-functionality of proteins involved in GPCR and G protein signaling: making sense of structure-function continuum with intrinsic disorder-based proteoforms. Cell Mol Life Sci. 2019; 76(22):4461-4492. PMC: 11105632. DOI: 10.1007/s00018-019-03276-1. View

Laun A, Shrader S, Brown K, Song Z . GPR3, GPR6, and GPR12 as novel molecular targets: their biological functions and interaction with cannabidiol. Acta Pharmacol Sin. 2018; 40(3):300-308. PMC: 6460361. DOI: 10.1038/s41401-018-0031-9. View

10.

Luo F, Rustay N, Ebert U, Hradil V, Cole T, Llano D . Characterization of 7- and 19-month-old Tg2576 mice using multimodal in vivo imaging: limitations as a translatable model of Alzheimer's disease. Neurobiol Aging. 2010; 33(5):933-44. DOI: 10.1016/j.neurobiolaging.2010.08.005. View

11.

Du X, Li Y, Xia Y, Ai S, Liang J, Sang P . Insights into Protein-Ligand Interactions: Mechanisms, Models, and Methods. Int J Mol Sci. 2016; 17(2). PMC: 4783878. DOI: 10.3390/ijms17020144. View

12.

Morano A, Cifelli P, Nencini P, Antonilli L, Fattouch J, Ruffolo G . Cannabis in epilepsy: From clinical practice to basic research focusing on the possible role of cannabidivarin. Epilepsia Open. 2018; 1(3-4):145-151. PMC: 5719834. DOI: 10.1002/epi4.12015. View

13.

Bunemann M, Hosey M . G-protein coupled receptor kinases as modulators of G-protein signalling. J Physiol. 1999; 517 ( Pt 1):5-23. PMC: 2269335. DOI: 10.1111/j.1469-7793.1999.0005z.x. View

14.

Zhang T, Faraggi E, Li Z, Zhou Y . Intrinsically semi-disordered state and its role in induced folding and protein aggregation. Cell Biochem Biophys. 2013; 67(3):1193-205. PMC: 3838602. DOI: 10.1007/s12013-013-9638-0. View

15.

Genin E, Plutino M, Bannwarth S, Villa E, Cisneros-Barroso E, Roy M . CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis. EMBO Mol Med. 2015; 8(1):58-72. PMC: 4718158. DOI: 10.15252/emmm.201505496. View

16.

Song H, Li H, Guo S, Pan Y, Fu Y, Zhou Z . Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease-associated phenotypes. Brain. 2018; 141(6):1782-1798. PMC: 5972579. DOI: 10.1093/brain/awy081. View

17.

Fox S . Non-dopaminergic treatments for motor control in Parkinson's disease. Drugs. 2013; 73(13):1405-15. DOI: 10.1007/s40265-013-0105-4. View

18.

Ambadipudi S, Zweckstetter M . Targeting intrinsically disordered proteins in rational drug discovery. Expert Opin Drug Discov. 2015; 11(1):65-77. DOI: 10.1517/17460441.2016.1107041. View

19.

Watkins L, Orlandi C . Orphan G Protein Coupled Receptors in Affective Disorders. Genes (Basel). 2020; 11(6). PMC: 7349732. DOI: 10.3390/genes11060694. View

20.

Sutton L, Orlandi C, Song C, Oh W, Muntean B, Xie K . Orphan receptor GPR158 controls stress-induced depression. Elife. 2018; 7. PMC: 5823542. DOI: 10.7554/eLife.33273. View