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Selective autophagy as a therapeutic target for neurological diseases.

ABSTRACT: The neurological diseases primarily include acute injuries, chronic neurodegeneration, and others (e.g., infectious diseases of the central nervous system). Autophagy is a housekeeping process responsible for the bulk degradation of misfolded protein aggregates and damaged organelles through the lysosomal machinery. Recent studies have suggested that autophagy, particularly selective autophagy, such as mitophagy, pexophagy, ER-phagy, ribophagy, lipophagy, etc., is closely implicated in neurological diseases. These forms of selective autophagy are controlled by a group of important proteins, including PTEN-induced kinase 1 (PINK1), Parkin, p62, optineurin (OPTN), neighbor of BRCA1 gene 1 (NBR1), and nuclear fragile X mental retardation-interacting protein 1 (NUFIP1). This review highlights the characteristics and underlying mechanisms of different types of selective autophagy, and their implications in various forms of neurological diseases.

SUBMITTER: Xu W

PROVIDER: S-EPMC7904548 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Selective autophagy as a therapeutic target for neurological diseases.

Xu Weilin W Ocak Umut U Gao Liansheng L Tu Sheng S Lenahan Cameron J CJ Zhang Jianmin J Shao Anwen A

Cellular and molecular life sciences : CMLS 20201016 4

The neurological diseases primarily include acute injuries, chronic neurodegeneration, and others (e.g., infectious diseases of the central nervous system). Autophagy is a housekeeping process responsible for the bulk degradation of misfolded protein aggregates and damaged organelles through the lysosomal machinery. Recent studies have suggested that autophagy, particularly selective autophagy, such as mitophagy, pexophagy, ER-phagy, ribophagy, lipophagy, etc., is closely implicated in neurologi ...[more]

PMID: 33067655

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Project description:Ubiquitination is a dynamic post-translational modification that regulates the fate of proteins and therefore modulates a myriad of cellular functions. At the last step of this sophisticated enzymatic cascade, E3 ubiquitin ligases selectively direct ubiquitin attachment to specific substrates. Altogether, the ?800 distinct E3 ligases, combined to the exquisite variety of ubiquitin chains and types that can be formed at multiple sites on thousands of different substrates confer to ubiquitination versatility and infinite possibilities to control biological functions. E3 ubiquitin ligases have been shown to regulate behaviors of proteins, from their activation, trafficking, subcellular distribution, interaction with other proteins, to their final degradation. Largely known for tagging proteins for their degradation by the proteasome, E3 ligases also direct ubiquitinated proteins and more largely cellular content (organelles, ribosomes, etc.) to destruction by autophagy. This multi-step machinery involves the creation of double membrane autophagosomes in which engulfed material is degraded after fusion with lysosomes. Cooperating in sustaining homeostasis, actors of ubiquitination, proteasome and autophagy pathways are impaired or mutated in wide range of human diseases. From initial discovery of pathogenic mutations in the E3 ligase encoding for E6-AP in Angelman syndrome and Parkin in juvenile forms of Parkinson disease, the number of E3 ligases identified as causal gene for neurological diseases has considerably increased within the last years. In this review, we provide an overview of these diseases, by classifying the E3 ubiquitin ligase types and categorizing the neurological signs. We focus on the Gigaxonin-E3 ligase, mutated in giant axonal neuropathy and present a comprehensive analysis of the spectrum of mutations and the recent biological models that permitted to uncover novel mechanisms of action. Then, we discuss the common functions shared by Gigaxonin and the other E3 ligases in cytoskeleton architecture, cell signaling and autophagy. In particular, we emphasize their pivotal roles in controlling multiple steps of the autophagy pathway. In light of the various targets and extending functions sustained by a single E3 ligase, we finally discuss the challenge in understanding the complex pathological cascade underlying disease and in designing therapeutic approaches that can apprehend this complexity.

Dataset Information

Selective autophagy as a therapeutic target for neurological diseases.

Publications

Selective autophagy as a therapeutic target for neurological diseases.

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