From Autophagy to Mitophagy: the Roles of P62 in Neurodegenerative Diseases

Overview

Journal J Bioenerg Biomembr

Publisher Springer

Specialties Biochemistry
Biology
Endocrinology

Date 2017 Oct 5

PMID 28975445

Citations 64

Authors

Haiying Liu

Chunqiu Dai

Yunlong Fan

Baolin Guo

Keke Ren

Tangna Sun

Wenting Wang

Affiliations

Soon will be listed here.

Abstract

P62, also called sequestosome1 (SQSTM1), is the selective cargo receptor for autophagy to degenerate misfolded proteins. It has also been found to assist and connect parkin in pink1/parkin mitophagy pathway. Previous studies showed that p62 was in association with neurodegenerative diseases, and one of the diseases pathogenesis is P62 induced autophagy and mitophagy dysfunction. Autophagy is an important process to eliminate misfolded proteins. Intracellular aggregation including α-synuclein, Huntingtin, tau protein and ß-amyloid (Aß) protein are the misfolded proteins found in PD, HD and AD, respectively. P62 induced autophagy failure significantly accelerates misfolded protein aggregation. Mitophagy is the special autophagy, functions as the selective scavenger towards the impaired mitochondria. Mitochondrial dysfunction was confirmed greatly contribute to the occurrence of neurodegenerative diseases. Through assistance and connection with parkin, P62 is vital for regulating mitophagy, thus, aberrant P62 could influence the balance of mitophagy, and further disturb mitochondrial quality control. Therefore, accumulation of misfolded proteins leads to the aberrant P62 expression, aberrant P62 influence the balance of mitophagy, forming a vicious circle afterwards. In this review, we summarize the observations on the function of P62 relevant to autophagy and mitophagy in neurodegenerative diseases, hoping to give some clear and objective opinions to further study.

Citing Articles

miR-448-3p/miR-1264-3p Participates in Intermittent Hypoxic Response in Hippocampus by Regulating Fam76b/hnRNPA2B1.

Liu C, Qu D, Li C, Pu W, Li J, Cai L CNS Neurosci Ther. 2025; 31(2):e70239.

PMID: 39912396 PMC: 11799915. DOI: 10.1111/cns.70239.

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.

Programmed cell death: molecular mechanisms, biological functions, diseases, and therapeutic targets.

Qian S, Long Y, Tan G, Li X, Xiang B, Tao Y MedComm (2020). 2024; 5(12):e70024.

PMID: 39619229 PMC: 11604731. DOI: 10.1002/mco2.70024.

Advanced glycation end-products accelerate amyloid deposits in adipocyte's lipid droplets.

Izgilov R, Kislev N, Omari E, Benayahu D Cell Death Dis. 2024; 15(11):846.

PMID: 39562539 PMC: 11577098. DOI: 10.1038/s41419-024-07211-6.

Poly-GP accumulation due to C9orf72 loss of function induces motor neuron apoptosis through autophagy and mitophagy defects.

de Calbiac H, Renault S, Haouy G, Jung V, Roger K, Zhou Q Autophagy. 2024; 20(10):2164-2185.

PMID: 39316747 PMC: 11423671. DOI: 10.1080/15548627.2024.2358736.

References

Lippai M, Low P . The role of the selective adaptor p62 and ubiquitin-like proteins in autophagy. Biomed Res Int. 2014; 2014:832704. PMC: 4075091. DOI: 10.1155/2014/832704. View

Zhou L, Wang H, Ren H, Chen D, Gao F, Hu Q . Bcl-2-dependent upregulation of autophagy by sequestosome 1/p62 in vitro. Acta Pharmacol Sin. 2013; 34(5):651-6. PMC: 3647217. DOI: 10.1038/aps.2013.12. View

Rui Y, Xu Z, Patel B, Chen Z, Chen D, Tito A . Huntingtin functions as a scaffold for selective macroautophagy. Nat Cell Biol. 2015; 17(3):262-75. PMC: 4344873. DOI: 10.1038/ncb3101. View

Goldberg A . Protein degradation and protection against misfolded or damaged proteins. Nature. 2003; 426(6968):895-9. DOI: 10.1038/nature02263. View

Kurosawa M, Matsumoto G, Kino Y, Okuno M, Kurosawa-Yamada M, Washizu C . Depletion of p62 reduces nuclear inclusions and paradoxically ameliorates disease phenotypes in Huntington's model mice. Hum Mol Genet. 2014; 24(4):1092-105. DOI: 10.1093/hmg/ddu522. View

Saitoh Y, Fujikake N, Okamoto Y, Popiel H, Hatanaka Y, Ueyama M . p62 plays a protective role in the autophagic degradation of polyglutamine protein oligomers in polyglutamine disease model flies. J Biol Chem. 2014; 290(3):1442-53. PMC: 4340391. DOI: 10.1074/jbc.M114.590281. View

Rue L, Lopez-Soop G, Gelpi E, Martinez-Vicente M, Alberch J, Perez-Navarro E . Brain region- and age-dependent dysregulation of p62 and NBR1 in a mouse model of Huntington's disease. Neurobiol Dis. 2013; 52:219-28. DOI: 10.1016/j.nbd.2012.12.008. View

Schaeffer V, Lavenir I, Ozcelik S, Tolnay M, Winkler D, Goedert M . Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain. 2012; 135(Pt 7):2169-77. PMC: 3381726. DOI: 10.1093/brain/aws143. View

Zhang Y, Gong J, Xing T, Zheng S, Ding W . Autophagy protein p62/SQSTM1 is involved in HAMLET-induced cell death by modulating apotosis in U87MG cells. Cell Death Dis. 2013; 4:e550. PMC: 3615731. DOI: 10.1038/cddis.2013.77. View

10.

Ivankovic D, Chau K, Schapira A, Gegg M . Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy. J Neurochem. 2015; 136(2):388-402. PMC: 4949652. DOI: 10.1111/jnc.13412. View

11.

Tsvetkov A, Miller J, Arrasate M, Wong J, Pleiss M, Finkbeiner S . A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model. Proc Natl Acad Sci U S A. 2010; 107(39):16982-7. PMC: 2947884. DOI: 10.1073/pnas.1004498107. View

12.

Johansen T, Lamark T . Selective autophagy mediated by autophagic adapter proteins. Autophagy. 2010; 7(3):279-96. PMC: 3060413. DOI: 10.4161/auto.7.3.14487. View

13.

Kim S, Lee D, Song J, Cho S, Yun S, Koh Y . NDP52 associates with phosphorylated tau in brains of an Alzheimer disease mouse model. Biochem Biophys Res Commun. 2014; 454(1):196-201. DOI: 10.1016/j.bbrc.2014.10.066. View

14.

Boyle K, Randow F . The role of 'eat-me' signals and autophagy cargo receptors in innate immunity. Curr Opin Microbiol. 2013; 16(3):339-48. DOI: 10.1016/j.mib.2013.03.010. View

15.

Lee H, Ahn H, Lee W, Oh Y, Choi H, Shim S . ENC1 Modulates the Aggregation and Neurotoxicity of Mutant Huntingtin Through p62 Under ER Stress. Mol Neurobiol. 2015; 53(10):6620-6634. DOI: 10.1007/s12035-015-9557-8. View

16.

Chen S, Zhou L, Zhang Y, Leng Y, Pei X, Lin H . Targeting SQSTM1/p62 induces cargo loading failure and converts autophagy to apoptosis via NBK/Bik. Mol Cell Biol. 2014; 34(18):3435-49. PMC: 4135623. DOI: 10.1128/MCB.01383-13. View

17.

Monzon S, Gili M, Vives M, Serrano M, Bauza N, Molina R . Melancholic versus non-melancholic depression: differences on cognitive function. A longitudinal study protocol. BMC Psychiatry. 2010; 10:48. PMC: 2896936. DOI: 10.1186/1471-244X-10-48. View

18.

Jung H, Kim Y, Eggert S, Chung K, Choi K, Park S . Age-dependent increases in tau phosphorylation in the brains of type 2 diabetic rats correlate with a reduced expression of p62. Exp Neurol. 2013; 248:441-50. DOI: 10.1016/j.expneurol.2013.07.013. View

19.

Tanji K, Odagiri S, Miki Y, Maruyama A, Nikaido Y, Mimura J . p62 Deficiency Enhances α-Synuclein Pathology in Mice. Brain Pathol. 2014; 25(5):552-64. PMC: 8029467. DOI: 10.1111/bpa.12214. View

20.

Huang S, Okamoto K, Yu C, Sinicrope F . p62/sequestosome-1 up-regulation promotes ABT-263-induced caspase-8 aggregation/activation on the autophagosome. J Biol Chem. 2013; 288(47):33654-33666. PMC: 3837112. DOI: 10.1074/jbc.M113.518134. View