Author response: Oligomerization of p62 allows for selection of ubiquitinated cargo and isolation membrane during selective autophagy

Wurzer, Bettina; Zaffagnini, Gabriele; Fracchiolla, Dorotea; Turco, Eleonora; Abert, Christine; Romanov, Julia; Martens, Sascha

doi:10.7554/elife.08941.024

Cited by 4 publications

(3 citation statements)

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“…The inclusions induced by fTau were observed to label with ThioS and anti-p62 antibody. Such labeling indicates the presence of amyloids that are recognized by the cell and targeted by p62 to the autolysosomal system for degradation (38)(39)(40). The labeling by both ThioS and anti-p62 antibody supports the hypothesis that exogenous fTau seeds endogenous fTau.…”

Section: Discussionsupporting

confidence: 55%

“…It is noteworthy that oligomerization is a normal common biological process that drives many signaling pathways. For instance, oligomerization is a necessary part in the activation of the proteins p53 and p62 (40)(41)(42)(43). However, disease-related accumulation of tau oligomers might stimulate the translational stress response as an indirect response to toxicity induced by tau oligomers.…”

Section: Discussionmentioning

confidence: 99%

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Tau Oligomers and Fibrils Exhibit Differential Patterns of Seeding and Association With RNA Binding Proteins

et al. 2020

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Tau aggregates are pleiotropic and exhibit differences in conformation, structure, and size. These aggregates develop endogenously but are also propagated among neurons in disease. We explored the actions of two distinct types of tau aggregates, tau oligomers (oTau) and tau fibrils (fTau), using a seeding assay in primary neuron cultures expressing human 4R0N tau. We find that oTau and fTau elicit distinct patterns of tau inclusions in the neurons and distinct molecular interactions. The exogenously applied oTau and fTau both clear rapidly from the neurons, but both also seed intracellular inclusions composed of endogenously produced tau. The two types of seeds elicit differential dose–response relationships for seed uptake and the number of resulting intracellular inclusions. Immunocytochemical studies show that co-localization with RNA binding proteins associated with stress granules is much greater for seeds composed of oTau than fTau. Conversely, co-localization with p62/SQSTM1 and thioflavine S is much greater for fTau than oTau. These results suggest that oTau seeds inclusions that modulate the translational stress response and are physiologically active, whereas fTau seeds inclusions that are fibrillar and shunted to the autolysosomal cascade.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Tau Oligomers and Fibrils Exhibit Differential Patterns of Seeding and Association With RNA Binding Proteins

et al. 2020

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“…During aggrephagy, adaptor proteins interact with LC3 and facilitate the formation of surrounding autophagosomes, leading to the sequestration and subsequent degradation of protein aggregates. Diverse regulatory mechanisms of adaptor protein activity have been shown to enhance aggrephagy, such as phosphorylation of specific residues ( Richter et al ., 2016 ; Turco et al ., 2019 ), oligomerization ( Wurzer et al ., 2015 ), and post-translational modifications ( McEwan and Dikic, 2011 ). Stimulating aggrephagy by modulating adaptor protein activity would be a beneficial approach for treating neurodegeneration.…”

Section: Selective Autophagy In Neuronsmentioning

confidence: 99%

Neuronal Autophagy: Characteristic Features and Roles in Neuronal Pathophysiology

Valencia

Kim

Jang

et al. 2021

Biomol Ther (Seoul)

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Autophagy is an important degradative pathway that eliminates misfolded proteins and damaged organelles from cells. Autophagy is crucial for neuronal homeostasis and function. A lack of or deficiency in autophagy leads to the accumulation of protein aggregates, which are associated with several neurodegenerative diseases. Compared with non-neuronal cells, neurons exhibit rapid autophagic flux because damaged organelles or protein aggregates cannot be diluted in post-mitotic cells; because of this, these cells exhibit characteristic features of autophagy, such as compartment-specific autophagy, which depends on polarized structures and rapid autophagy flux. In addition, neurons exhibit compartment-specific autophagy, which depends on polarized structures. Neuronal autophagy may have additional physiological roles other than amino acid recycling. In this review, we focus on the characteristics and regulatory factors of neuronal autophagy. We also describe intracellular selective autophagy in neurons and its association with neurodegenerative diseases.

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Autophagy preferentially degrades non-fibrillar polyQ aggregates

Zhao

Bäuerlein

Saha

et al. 2023

Preprint

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Aggregation of proteins containing expanded polyglutamine (polyQ) repeats is the cytopathologic hallmark of a group of dominantly inherited neurodegenerative diseases, including Huntington's disease (HD). Huntingtin (Htt), the disease protein of HD, forms amyloid-like fibrils by liquid-to-solid phase transition. Macroautophagy has been proposed to clear polyQ aggregates, but the efficiency of aggrephagy is limited. Here, we used cryo-electron tomography to visualize the interactions of autophagosomes with polyQ aggregates in cultured cells in situ. We found that an amorphous aggregate phase exists next to the radially organized polyQ fibrils. Autophagosomes preferentially engulfed this amorphous material, mediated by interactions between the autophagy receptor p62/SQSTM1 and the non-fibrillar aggregate surface. In contrast, amyloid fibrils excluded p62 and evaded clearance, resulting in trapping of autophagic structures. These results suggest that the limited efficiency of autophagy in clearing polyQ aggregates is due to the inability of autophagosomes to interact productively with the non-deformable, fibrillar disease aggregates.

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Author response: Oligomerization of p62 allows for selection of ubiquitinated cargo and isolation membrane during selective autophagy

Cited by 4 publications

References 0 publications

Tau Oligomers and Fibrils Exhibit Differential Patterns of Seeding and Association With RNA Binding Proteins

Tau Oligomers and Fibrils Exhibit Differential Patterns of Seeding and Association With RNA Binding Proteins

Neuronal Autophagy: Characteristic Features and Roles in Neuronal Pathophysiology

Autophagy preferentially degrades non-fibrillar polyQ aggregates

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