James A. Conway

Emerging evidence suggests that Parkinson’s disease (PD) may have its origin in the enteric nervous system (ENS), from where α-synuclein (αS) pathology spreads to the brain^1,2,3,4. Decades before the onset of motor symptoms, patients with PD suffer from constipation and present with circulating T cells responsive to αS, suggesting that peripheral immune responses initiated in the ENS may be involved in the early stages of PD^1,5,6,7. However, cellular mechanisms that trigger αS pathology in the ENS and its spread along the gut–brain axis remain elusive. Here we demonstrate that muscularis macrophages (ME-Macs), housekeepers of ENS integrity and intestinal homeostasis, modulate αS pathology and neurodegeneration in models of PD^8,9. ME-Macs contain misfolded αS, adopt a signature reflecting endolysosomal dysfunction and modulate the expansion of T cells that travel from the ENS to the brain through the dura mater as αS pathology progresses. Directed ME-Mac depletion leads to reduced αS pathology in the ENS and central nervous system, prevents T cell expansion and mitigates neurodegeneration and motor dysfunction, suggesting a role for ME-Macs as early cellular initiators of αS pathology along the gut–brain axis. Understanding these mechanisms could pave the way for early-stage biomarkers in PD.

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 SCF^FXBL5 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.

The neurotrophic signaling of glial cell line-derived neurotrophic factor (GDNF) with its canonical receptor, the receptor tyrosine kinase RET, coupled together with the GDNF family receptor alpha 1 is important for dopaminergic neuron survival and physiology in cell culture experiments and animal models. This prompted the idea to try GDNF/RET signaling as a therapeutic approach to treat Parkinson’s disease with the hallmark of dopaminergic cell death in the substantia nigra of the midbrain. Despite several clinical trials with GDNF in Parkinson’s disease patients, which mainly focused on optimizing the GDNF delivery technique, benefits were only seen in a few patients. In general, the endpoints did not show significant improvements. This suggests that it will be helpful to learn more about the basic biology of this fascinating but complicated GDNF/RET signaling system in the dopaminergic midbrain and about recent developments in the field to facilitate its use in the clinic. Here we will refer to the latest publications and point out important open questions in the field.

The glial cell line–derived neurotrophic factor (GDNF) and its canonical receptor Ret can signal both in tandem and separately to exert many vital functions in the midbrain dopamine system. It is known that Ret has effects on maintenance, physiology, protection and regeneration in the midbrain dopamine system, with the physiological functions of GDNF still somewhat unclear. Notwithstanding, Ret ligands, such as GDNF, are considered as promising candidates for neuroprotection and/or regeneration in Parkinson’s disease, although data from clinical trials are so far inconclusive. In this review, we discuss the current knowledge of GDNF/Ret signaling in the dopamine system in vivo as well as crosstalk with pathology-associated proteins and their signaling in mammals.