Protein Misfolding and ER Stress in Huntington's Disease

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2019 Apr 20

PMID 31001537

Citations 51

Authors

Talya Shacham

Neeraj Sharma

Gerardo Z Lederkremer

Affiliations

Soon will be listed here.

Abstract

Increasing evidence in recent years indicates that protein misfolding and aggregation, leading to ER stress, are central factors of pathogenicity in neurodegenerative diseases. This is particularly true in Huntington's disease (HD), where in contrast with other disorders, the cause is monogenic. Mutant huntingtin interferes with many cellular processes, but the fact that modulation of ER stress and of the unfolded response pathways reduces the toxicity, places these mechanisms at the core and gives hope for potential therapeutic approaches. There is currently no effective treatment for HD and it has a fatal outcome a few years after the start of symptoms of cognitive and motor impairment. Here we will discuss recent findings that shed light on the mechanisms of protein misfolding and aggregation that give origin to ER stress in neurodegenerative diseases, focusing on Huntington's disease, on the cellular response and on how to use this knowledge for possible therapeutic strategies.

Citing Articles

Calvo B, Schembri-Wismayer P, Duran-Alonso M Cells. 2025; 14(5).

PMID: 40072076 PMC: 11898746. DOI: 10.3390/cells14050347.

Neurons Specialize in Presynaptic Autophagy: A Perspective to Ameliorate Neurodegeneration.

Mishra A, Tripathi M, Kumar D, Gupta S Mol Neurobiol. 2024; 62(2):2626-2640.

PMID: 39141193 DOI: 10.1007/s12035-024-04399-8.

The Role of NRF2 in Trinucleotide Repeat Expansion Disorders.

Chang K, Chen C Antioxidants (Basel). 2024; 13(6).

PMID: 38929088 PMC: 11200942. DOI: 10.3390/antiox13060649.

Polyglutamine-mediated ribotoxicity disrupts proteostasis and stress responses in Huntington's disease.

Aviner R, Lee T, Masto V, Li K, Andino R, Frydman J Nat Cell Biol. 2024; 26(6):892-902.

PMID: 38741019 DOI: 10.1038/s41556-024-01414-x.

Impact of Obesity-Related Endoplasmic Reticulum Stress on Cancer and Associated Molecular Targets.

AlBashtawi J, Al-Jaber H, Ahmed S, Al-Mansoori L Biomedicines. 2024; 12(4).

PMID: 38672148 PMC: 11047871. DOI: 10.3390/biomedicines12040793.

References

Kuemmerle S, Gutekunst C, Klein A, Li X, Li S, Beal M . Huntington aggregates may not predict neuronal death in Huntington's disease. Ann Neurol. 1999; 46(6):842-9. View

Kazemi-Esfarjani P, Benzer S . Genetic suppression of polyglutamine toxicity in Drosophila. Science. 2000; 287(5459):1837-40. DOI: 10.1126/science.287.5459.1837. View

Zoghbi H, Orr H . Glutamine repeats and neurodegeneration. Annu Rev Neurosci. 2000; 23:217-47. DOI: 10.1146/annurev.neuro.23.1.217. View

Dinner A, Sali A, Smith L, Dobson C, Karplus M . Understanding protein folding via free-energy surfaces from theory and experiment. Trends Biochem Sci. 2000; 25(7):331-9. DOI: 10.1016/s0968-0004(00)01610-8. View

Novoa I, Zeng H, Harding H, Ron D . Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol. 2001; 153(5):1011-22. PMC: 2174339. DOI: 10.1083/jcb.153.5.1011. View

Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K . XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2002; 107(7):881-91. DOI: 10.1016/s0092-8674(01)00611-0. View

Hartl F, Hayer-Hartl M . Molecular chaperones in the cytosol: from nascent chain to folded protein. Science. 2002; 295(5561):1852-8. DOI: 10.1126/science.1068408. View

Bucciantini M, Giannoni E, Chiti F, Baroni F, Formigli L, Zurdo J . Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature. 2002; 416(6880):507-11. DOI: 10.1038/416507a. View

Meriin A, Zhang X, He X, Newnam G, Chernoff Y, Sherman M . Huntington toxicity in yeast model depends on polyglutamine aggregation mediated by a prion-like protein Rnq1. J Cell Biol. 2002; 157(6):997-1004. PMC: 2174031. DOI: 10.1083/jcb.200112104. View

10.

Taylor J, Hardy J, Fischbeck K . Toxic proteins in neurodegenerative disease. Science. 2002; 296(5575):1991-5. DOI: 10.1126/science.1067122. View

11.

Shen J, Chen X, Hendershot L, Prywes R . ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell. 2002; 3(1):99-111. DOI: 10.1016/s1534-5807(02)00203-4. View

12.

Murphy R . Peptide aggregation in neurodegenerative disease. Annu Rev Biomed Eng. 2002; 4:155-74. DOI: 10.1146/annurev.bioeng.4.092801.094202. View

13.

Keene C, Rodrigues C, Eich T, Chhabra M, Steer C, Low W . Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. Proc Natl Acad Sci U S A. 2002; 99(16):10671-6. PMC: 125009. DOI: 10.1073/pnas.162362299. View

14.

Sakahira H, Breuer P, Hartl F . Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proc Natl Acad Sci U S A. 2002; 99 Suppl 4:16412-8. PMC: 139902. DOI: 10.1073/pnas.182426899. View

15.

Ron D . Translational control in the endoplasmic reticulum stress response. J Clin Invest. 2002; 110(10):1383-8. PMC: 151821. DOI: 10.1172/JCI16784. View

16.

Soto C . Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci. 2003; 4(1):49-60. DOI: 10.1038/nrn1007. View

17.

Hayashi T, Su T . Intracellular dynamics of sigma-1 receptors (sigma(1) binding sites) in NG108-15 cells. J Pharmacol Exp Ther. 2003; 306(2):726-33. DOI: 10.1124/jpet.103.051292. View

18.

Rosas H, Koroshetz W, Chen Y, Skeuse C, Vangel M, Cudkowicz M . Evidence for more widespread cerebral pathology in early HD: an MRI-based morphometric analysis. Neurology. 2003; 60(10):1615-20. DOI: 10.1212/01.wnl.0000065888.88988.6e. View

19.

Vendruscolo M, Zurdo J, MacPhee C, Dobson C . Protein folding and misfolding: a paradigm of self-assembly and regulation in complex biological systems. Philos Trans A Math Phys Eng Sci. 2003; 361(1807):1205-22. DOI: 10.1098/rsta.2003.1194. View

20.

Cullinan S, Zhang D, Hannink M, Arvisais E, Kaufman R, Diehl J . Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol. 2003; 23(20):7198-209. PMC: 230321. DOI: 10.1128/MCB.23.20.7198-7209.2003. View