p62 Deficiency Enhances α‐Synuclein Pathology in Mice

Abstract

In Lewy body disease (LBD) such as dementia with LBs and Parkinson's disease, several lines of evidence show that disrupted proteolysis occurs. p62/SQSTM1 (p62) is highly involved with intracellular proteolysis and is a component of ubiquitin-positive inclusions in various neurodegenerative disorders. However, it is not clear whether p62 deficiency affects inclusion formation and abnormal protein accumulation. To answer this question, we used a mouse model of LBD that lacks p62, and found that LB-like inclusions were observed in transgenic mice that overexpressed α-synuclein (Tg mice) with or without the p62 protein. p62 deficiency enhanced α-synuclein pathology with regard to the number of inclusions and staining intensity compared with Tg mice that expressed p62. To further investigate the molecular mechanisms associated with the loss of p62 in Tg mice, we assessed the mRNA and protein levels of several molecules, and found that the neighbor of the brca1 gene (NBr1), which is functionally and structurally similar to p62, is increased in Tg mice without p62 compared with control Tg mice. These findings suggest that p62 and NBR1 affect the pathogenesis of neurodegenerative diseases through the cooperative modulation of α-synuclein aggregation.

Toll-like receptor 2 is increased in neurons in Parkinson’s disease brain and may contribute to alpha-synuclein pathology

“…This suggested a potential defect in the turnover of α-synuclein protein, which is not clearly understood but involves both proteosomal and lysosmal degradation [46]. We did not find differences in the autophagy markers beclin1 or LC3 following TLR2 activation; however, we did find that TLR2 activation increased the levels of p62/SQSTIM1, a receptor for selective autophagy of target proteins potentially including α-synuclein [22, 42, 45], that is known to increase when autophagy/lysosmal pathways are impaired. Interestingly, activation of autophagy with rapamycin was able to ameliorate the TLR2-mediated increase in α-synuclein, suggesting that activating autophagy can help clear α-synuclein protein, as has been seen before in animal studies [2, 23, 25, 32].…”

p62/SQSTM1 – steering the cell through health and disease

“…Multiple lines of evidence also link SQSTM1 with the pathophysiology of Parkinson's disease (PD). Loss of SQSTM1 results in increased accumulation and phosphorylation of αsynuclein (SNCA), a molecular hallmark of the disease (Tanji et al, 2015). Mutations in LRRK2 are responsible for the most common monogenic form of PD, as mutant LRRK2 dysregulates the formation of protein aggregates and their autophagic degradation during the disease (Bang et al, 2016;Bravo-San Pedro et al, 2012).…”

Repurposing the NRF2 Activator Dimethyl Fumarate as Therapy Against Synucleinopathy in Parkinson's Disease

“…For the purpose of this study, we focused on autophagy. We analyzed the levels of autophagosome cargo protein p62, because its expression is regulated by NRF2 (32,41) and it has been reported to participate in autophagy of a-SYN (66,74). We also analyzed LC3, a protein specifically associated with autophagic vesicles whose lipidized levels (LC3-II) correlate with autophagosome abundance.…”

“…Asterisks denote significant differences *p < 0.05 and **p < 0.01, comparing the indicated groups. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars 66 LASTRES-BECKER ET AL.…”