p62 Plays a Protective Role in the Autophagic Degradation of Polyglutamine Protein Oligomers in Polyglutamine Disease Model Flies

Abstract

Background: Oligomers of pathogenic proteins are implicated in the pathomechanisms of neurodegenerative diseases. Results: Depletion of p62 delays the degradation of polyglutamine protein oligomers via autophagy and exacerbates neurodegeneration in polyglutamine disease model flies. Conclusion: p62 plays a protective role via autophagic degradation of polyglutamine protein oligomers. Significance: p62 should be a therapeutic target for the polyglutamine diseases.

A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism

“…Moreover, p62 was also able to reduce TDP43 aggregation [5]. Similarly, overexpression of p62 is beneficial in other neurodegenerative diseases [20,40]. Hence, these data suggest that the observed increase in p62 in some C9orf72 models probably represents an attempted beneficial compensatory upregulation by the cell.…”

Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway

“…The levels of p62, which incorporates into autophagosomes and efficiently degraded [25] were instead decreased (0.51±0.06 fold vs. non-diabetic, P<0.01, Figure 1B). This was associated with significant increase in the pro-apoptotic phospho Bcl-2 ( Figure 1C) and caspase-3/7 activity A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 11 (2.7±0.1 fold vs. non-diabetic, P<0.05, Figure 1D) which was confirmed by increased TUNEL-positive cardiomyocytes in diabetic heart (5.4±1.3 vs. 2.1±0.64, P<0.05 vs. nondiabetic, Figure 1E).…”

Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice

“…Previous studies have shown that p62 localizes to protein aggregates in many neurodegenerative diseases including SCA3 and may play a protective role in autophagic clearance of polyglutamine disease proteins 28,29,41,42 . By immunoblot analysis, diencephalic (Fig 7C and 7E) and cerebellar (Fig 7F and 7H) p62 expression levels did not differ across vehicle-treated WT, vehicle-treated Q84/Q84, or ASO-5 treated mice.…”