Activating Autophagy As a Therapeutic Strategy for Parkinson's Disease

Overview

Journal CNS Drugs

Specialties Neurology
Pharmacology

Date 2018 Mar 2

PMID 29492779

Citations 22

Authors

Alan J Fowler

Charbel E-H Moussa

Affiliations

Soon will be listed here.

Abstract

Parkinson's disease is a progressive neurodegenerative disease characterized by Lewy body pathology of which the primary constituent is aggregated misfolded alpha-synuclein protein. Currently, there are no clinical therapies for treatment of the underlying alpha-synuclein dysfunction and accumulation, and the standard of care for patients with Parkinson's disease focuses only on symptom management, creating an immense therapeutic gap that needs to be filled. Defects in autophagy have been strongly implicated in Parkinson's disease. Here, we review evidence from human, mouse, and cell culture studies to briefly explain these defects in autophagy in Parkinson's disease and the necessity for autophagy to be carefully and precisely tuned to maintain neuron survival. We summarize recent experimental agents for treating alpha-synuclein accumulation in α-synuclein Parkinson's disease and related synucleinopathies. Most of the efforts for developing experimental agents have focused on immunotherapeutic strategies, but we discuss why those efforts are misplaced. Finally, we emphasize why increasing autophagy flux for alpha-synuclein clearance is the most promising therapeutic strategy. Activating autophagy has been successful in preclinical models of Parkinson's disease and yields promising results in clinical trials.

Citing Articles

TFE3-mediated neuroprotection: Clearance of aggregated α-synuclein and accumulated mitochondria in the AAV-α-synuclein model of Parkinson's disease.

He X, Chen M, Fan Y, Wu B, Dong Z Genes Dis. 2025; 12(2):101429.

PMID: 39759118 PMC: 11697191. DOI: 10.1016/j.gendis.2024.101429.

Dopamine- and Grape-Seed-Extract-Loaded Solid Lipid Nanoparticles: Interaction Studies between Particles and Differentiated SH-SY5Y Neuronal Cell Model of Parkinson's Disease.

Mallamaci R, Musaro D, Greco M, Caponio A, Castellani S, Munir A Molecules. 2024; 29(8).

PMID: 38675592 PMC: 11051794. DOI: 10.3390/molecules29081774.

Inhibition of the TLR/NF-B Signaling Pathway and Improvement of Autophagy Mediates Neuroprotective Effects of Plumbagin in Parkinson's Disease.

Su Y, Li M, Wang Q, Xu X, Qin P, Huang H Oxid Med Cell Longev. 2023; 2022:1837278.

PMID: 36589679 PMC: 9800084. DOI: 10.1155/2022/1837278.

Alteration of Autophagy and Glial Activity in Nilotinib-Treated Huntington's Disease Patients.

Anderson K, Stevenson M, Varghese R, Hebron M, Koppel E, McCartin M Metabolites. 2022; 12(12).

PMID: 36557263 PMC: 9781133. DOI: 10.3390/metabo12121225.

Ursolic acid enhances autophagic clearance and ameliorates motor and non-motor symptoms in Parkinson's disease mice model.

Bang Y, Kwon Y, Kim M, Moon S, Jung K, Choi H Acta Pharmacol Sin. 2022; 44(4):752-765.

PMID: 36138143 PMC: 10042858. DOI: 10.1038/s41401-022-00988-2.

References

Rosen K, Moussa C, Lee H, Kumar P, Kitada T, Qin G . Parkin reverses intracellular beta-amyloid accumulation and its negative effects on proteasome function. J Neurosci Res. 2009; 88(1):167-78. PMC: 2844439. DOI: 10.1002/jnr.22178. View

Okamoto K, Kondo-Okamoto N, Ohsumi Y . Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy. Dev Cell. 2009; 17(1):87-97. DOI: 10.1016/j.devcel.2009.06.013. View

Polymenidou M, Cleveland D . Prion-like spread of protein aggregates in neurodegeneration. J Exp Med. 2012; 209(5):889-93. PMC: 3348110. DOI: 10.1084/jem.20120741. View

Herman A, Moussa C . The ubiquitin ligase parkin modulates the execution of autophagy. Autophagy. 2011; 7(8):919-21. DOI: 10.4161/auto.7.8.15814. View

Khandelwal P, Dumanis S, Feng L, Maguire-Zeiss K, Rebeck G, Lashuel H . Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model. Mol Neurodegener. 2010; 5:47. PMC: 2987994. DOI: 10.1186/1750-1326-5-47. View

Geisler S, Holmstrom K, Skujat D, Fiesel F, Rothfuss O, Kahle P . PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol. 2010; 12(2):119-31. DOI: 10.1038/ncb2012. View

He C, Klionsky D . Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009; 43:67-93. PMC: 2831538. DOI: 10.1146/annurev-genet-102808-114910. View

Ciechanover A, Kwon Y . Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med. 2015; 47:e147. PMC: 4351408. DOI: 10.1038/emm.2014.117. View

Kanki T, Wang K, Cao Y, Baba M, Klionsky D . Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev Cell. 2009; 17(1):98-109. PMC: 2746076. DOI: 10.1016/j.devcel.2009.06.014. View

10.

Winslow A, Rubinsztein D . Autophagy in neurodegeneration and development. Biochim Biophys Acta. 2008; 1782(12):723-9. PMC: 2597715. DOI: 10.1016/j.bbadis.2008.06.010. View

11.

Koyano F, Okatsu K, Kosako H, Tamura Y, Go E, Kimura M . Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature. 2014; 510(7503):162-6. DOI: 10.1038/nature13392. View

12.

Jimenez-Mateos E, Gonzalez-Billault C, Dawson H, Vitek M, Avila J . Role of MAP1B in axonal retrograde transport of mitochondria. Biochem J. 2006; 397(1):53-9. PMC: 1479764. DOI: 10.1042/BJ20060205. View

13.

Sutovsky P, Moreno R, Ramalho-Santos J, Dominko T, Simerly C, Schatten G . Ubiquitin tag for sperm mitochondria. Nature. 1999; 402(6760):371-2. DOI: 10.1038/46466. View

14.

Wong E, Tan J, Soong W, Hussein K, Nukina N, Dawson V . Autophagy-mediated clearance of aggresomes is not a universal phenomenon. Hum Mol Genet. 2008; 17(16):2570-82. PMC: 2722889. DOI: 10.1093/hmg/ddn157. View

15.

Xilouri M, Vogiatzi T, Vekrellis K, Park D, Stefanis L . Abberant alpha-synuclein confers toxicity to neurons in part through inhibition of chaperone-mediated autophagy. PLoS One. 2009; 4(5):e5515. PMC: 2677735. DOI: 10.1371/journal.pone.0005515. View

16.

Kanazawa T, Taneike I, Akaishi R, Yoshizawa F, Furuya N, Fujimura S . Amino acids and insulin control autophagic proteolysis through different signaling pathways in relation to mTOR in isolated rat hepatocytes. J Biol Chem. 2003; 279(9):8452-9. DOI: 10.1074/jbc.M306337200. View

17.

Kegel K, Kim M, Sapp E, McIntyre C, Castano J, Aronin N . Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. J Neurosci. 2000; 20(19):7268-78. PMC: 6772788. View

18.

Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S . Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000; 25(3):302-5. DOI: 10.1038/77060. View

19.

Lashuel H, Overk C, Oueslati A, Masliah E . The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci. 2012; 14(1):38-48. PMC: 4295774. DOI: 10.1038/nrn3406. View

20.

Ravikumar B, Vacher C, Berger Z, Davies J, Luo S, Oroz L . Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004; 36(6):585-95. DOI: 10.1038/ng1362. View