Abstract

Parkinson’s disease (PD) is a debilitating neurodegenerative disease that causes a great clinical burden. However, its exact molecular pathologies are not fully understood. Whilst there are a number of avenues for research into slowing, halting, or reversing PD, one central idea is to enhance the clearance of the proposed aetiological protein, oligomeric α-synuclein. Oligomeric α-synuclein is the main constituent protein in Lewy bodies and neurites and is considered neurotoxic. Multiple E3 ubiquitin-protein ligases, including the NEDD4 (neural precursor cell expressed developmentally downregulated protein 4) family, parkin, SIAH (mammalian homologues of Drosophila seven in absentia), CHIP (carboxy-terminus of Hsc70 interacting protein), and SCFFXBL5 SCF ubiquitin ligase assembled by the S-phase kinase-associated protein (SKP1), cullin-1 (Cul1), a zinc-binding RING finger protein, and the F-box domain/Leucine-rich repeat protein 5-containing protein FBXL5), have been shown to be able to ubiquitinate α-synuclein, influencing its subsequent degradation via the proteasome or lysosome. Here, we explore the link between NEDD4 ligases and PD, which is not only via α-synuclein but further strengthened by several additional substrates and interaction partners. Some members of the NEDD4 family of ligases are thought to crosstalk even with PD-related genes and proteins found to be mutated in familial forms of PD. Mutations in NEDD4 family genes have not been observed in PD patients, most likely because of their essential survival function during development. Following further in vivo studies, it has been thought that NEDD4 ligases may be viable therapeutic targets in PD. NEDD4 family members could clear toxic proteins, enhancing cell survival and slowing disease progression, or might diminish beneficial proteins, reducing cell survival and accelerating disease progression. Here, we review studies to date on the expression and function of NEDD4 ubiquitin ligases in the brain and their possible impact on PD pathology.

Highlights

  • Parkinson’s disease (PD) is characterised by the loss of midbrain dopaminergic neurons in the substantia nigra, which is frequently accompanied by an accumulation of α-synuclein in β-sheet filaments in these neurons and neurites [1]

  • Genes 2022, 13, 513 α-synuclein, it has been proposed that the non-ubiquitinated protein might be slowly degraded by autophagy, the monoubiquitinated protein might be degraded by the propteoalysoumbieq,uaintidnathtedpoplryoutebinqumitianyatbeeddpergorteaidnemd abyybtehedepgrroatdeeadsobmyethaendprloytseoasome a[4n,d8]l.y-αssyonsoumclei[n4,c8a].nαb-seyunbuicqlueiintincaantebdeounbinqiunietindaiftfeedreonnt nlyinseindeifrfeesriednutelys,silnyesirneessid6u, e1s0,ly12si,n2e1s,62,3, 3120, 3142, 4213,a2n3d, 3926,3w4,i4th3 adnifdfe9r6e,nwt pitrhedfeirffeenrceenst ipnremfeornenocmeseriinc,moolingoommeerricic,oalingdomagegrirce,gaantded αa-gsgyrneugaclteidn,αa-syNn-utcelremini,nasl mNo-tneormubiniqaul imtinoantoiounbisqtuimitiunlaattieosnasgtgimreuglaatieosnaagngdrepgraotitoenasaonmdal dpergorteaadsaotmioanl[d4e,5g]r.adation [4,5]

  • After summarising the different E3 ubiquitin–protein ligases, which have been suggested to use α-synuclein as a substrate, we focus on one group of them—the NEDD4 family, which has many additional PD-linked substrates—and support the idea that NEDD4 family members can be considered as therapeutic targets to treat PD

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Summary

Introduction

Parkinson’s disease (PD) is characterised by the loss of midbrain dopaminergic neurons in the substantia nigra, which is frequently accompanied by an accumulation of α-synuclein in β-sheet filaments in these neurons (so-called Lewy bodies) and neurites [1]. This aggregation process is thought to underlie the disease’s toxicity, with intermediate α-synuclein oligomers being the toxic agent [1]. The accumulation of misfolded α-synuclein in PD is considered to be due to increased expression [2,3] or reduced degradation via the ubiquitin proteasome, the lysosome, and the autophagy system [4,5]. For α-synuclein, it has been proposed that the non-ubiquitinated protein might be slowly degraded by autophagy, the monoubiquitinated protein might be degraded by the proteasome, and the. After summarising the different E3 ubiquitin–protein ligases, which have been suggested to use α-synuclein as a substrate, we focus on one group of them—the NEDD4 family, which has many additional PD-linked substrates—and support the idea that NEDD4 family members can be considered as therapeutic targets to treat PD

E3 Ligases Ubiquitinating α-Synuclein
NEDD4-1 and NEDD4-2 Expression
NEDD4-1 and NEDD4-2 Structure und Posttranslational Modifications
Findings
Conclusions and Future Directions
Full Text
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