Novel Immunotherapeutic Approaches to Target Alpha-Synuclein and Related Neuroinflammation in Parkinson’s Disease

Abstract

The etiology of Parkinson’s disease (PD) is significantly influenced by disease-causing changes in the protein alpha-Synuclein (aSyn). It can trigger and promote intracellular stress and thereby impair the function of dopaminergic neurons. However, these damage mechanisms do not only extend to neuronal cells, but also affect most glial cell populations, such as astroglia and microglia, but also T lymphocytes, which can no longer maintain the homeostatic CNS milieu because they produce neuroinflammatory responses to aSyn pathology. Through precise neuropathological examination, molecular characterization of biomaterials, and the use of PET technology, it has been clearly demonstrated that neuroinflammation is involved in human PD. In this review, we provide an in-depth overview of the pathomechanisms that aSyn elicits in models of disease and focus on the affected glial cell and lymphocyte populations and their interaction with pathogenic aSyn species. The interplay between aSyn and glial cells is analyzed both in the basic research setting and in the context of human neuropathology. Ultimately, a strong rationale builds up to therapeutically reduce the burden of pathological aSyn in the CNS. The current antibody-based approaches to lower the amount of aSyn and thereby alleviate neuroinflammatory responses is finally discussed as novel therapeutic strategies for PD.

On the Neuroprotective Effects of Naringenin: Pharmacological Targets, Signaling Pathways, Molecular Mechanisms, and Clinical Perspective

“…PD is characterized by activated microglia and intracytoplasmic eosinophilic proteinaceous inclusions known as Lewy bodies which are made up of alpha-synuclein self-aggregation in substantia nigra (SN) neurons [67]. Oxidative insults, dopamine depletion, and neuroinflammation play a critical role in the induction and progression of this type of NDs [68,69]. Due to the potential dopamine enhancing, potent antioxidant as well as anti-inflammatory effects of naringenin, it could be used as a beneficial agent in the treatment of PD [70].…”

CXCL12 is involved in α-synuclein-triggered neuroinflammation of Parkinson’s disease

“…Histological degeneration of dopaminergic neurons in the substantia nigra (SN) and the formation of Lewy bodies (LBs) containing aggregates of α-synuclein are the main neuropathological hallmarks. The underlying pathogenetic mechanism of PD remains elusive, but recent opinions and perspectives on the subject have focused on the inflammation process induced by microglia in the SN, which contributes to α-synuclein-mediated toxicity [2–4]. One hypothesis is that the course of PD may spiral out of control with excessive microglial activation and overproduction of cytokines and other inflammatory mediators [5].…”

The role of natural killer cells in Parkinson’s disease

“…This interaction can induce decreased expression of the MHC class I molecule Qa1 on activated microglia, which in turn triggers NK cell-mediated cytotoxicity towards hyperactive microglia 69 . As microglia are known to become aberrantly activated in the presence of sustained α-syn burden, targeting microglial activation states by suppressing their deleterious proinflammatory neurotoxicity may be a valid therapeutic approach for PD treatment 23 . Therefore, NK cells could exert protection by mitigating microglial toxic effects within the CNS.…”

“…Extracellular α-syn aggregates may elicit a selfamplifying cycle of immune responses in the CNS 14,18 and periphery 19 through an overproduction of inflammatory mediators, thus providing the tertiary hit required for PDassociated dysfunction to spread to neighboring neurons in the CNS 20,21 and the periphery 22 . Therefore, immunomodulatory-based approaches aimed at halting the propagation and burden of extracellular α-syn, and in turn diminishing the inflammatory response, are currently being tested as a therapeutic for PD and related synucleinopathies (reviewed in 23 ). Recently, it was discovered that natural killer (NK) cells efficiently internalize and degrade α-syn aggregates via the endosomal/lysosomal pathway, a novel and highly relevant function of NK cells in synucleinopathies 24 .…”