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.
Highlights
Parkinson’s disease (PD) is the second-most common neurodegenerative disorder and affects2–3% of the general population with an age of more than 65 years
Local overexpression of aSyn in midbrain neurons by viral vectors led to dopaminergic neurodegeneration [30], which was shown to be associated with a locally significantly increased proliferation of T and B lymphocytes being accompanied with microglial activation [49]
It is undisputed that neuroinflammatory processes are significantly associated with the neuropathological progression and clinical course of PD
Summary
Parkinson’s disease (PD) is the second-most common neurodegenerative disorder and affects. 2–3% of the general population with an age of more than 65 years It is characterized by a multitude of pathophysiological alterations that are linked to the dysfunctional state of the protein alpha-Synuclein (aSyn). After intensive research over the last decades, it is generally accepted that aSyn pathology is tightly associated with CNS neuroinflammation in PD The evidence for this phenomenon extends over basic science studies in cell culture or animal models to increasing data by human examinations, which have been collected post mortem and in vivo [7]. The interactions of aSyn with astroglia, monocytes and microglia, and T lymphocytes are depicted and resulting cellular pathologies and their associated pathomechanisms are discussed These findings are related to human neuropathological data and analyzed for their significance, and plausibility. The preclinical results and designs of current human studies employing anti-aSyn directed antibodies as immunotherapy for PD will be presented and evaluated in a look-ahead for future developments
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