α‐Synuclein in Neurodegeneration—A Good Protein that may go Bad

Parkinsonian disorders represent a large group of age‐related neurodegenerative diseases. In addition to common Parkinson's disease (PD), they include the more rare atypical parkinsonian disorders, such as multiple system atrophy (MSA), progressive supranuclear palsy, corticobasal degeneration, and dementia with Lewy bodies (DLB) 10. The differential diagnosis may be challenging, especially in early disease stages. As an accurate initial diagnosis has profound implications for the management of these devastating disorders, there is an unmet need for better diagnostic tools. Additionally, biomarkers are critical in objectively evaluating PD progression and assessing treatment effects. More knowledge is also needed on pathogenic mechanisms.

Predominantly expressed in the pre‐synapse, 140 amino acid‐long α‐synuclein has been found to be the major constituent of the intracellular aggregates in Lewy bodies, the pathological hallmark of PD and DLB, and in the glial cytoplasmic inclusions of MSA 4, 9. These diseases have accordingly been grouped as synucleinopathies, which differentiates them from the other parkinsonian disorders. Intracellular α‐synuclein has been shown to be released into the extracellular space 2 and may be transmitted between neurons 1. The exact role of α‐synuclein in neurotoxicity remains unclear but genetic data (duplications and triplications of the α‐synuclein‐encoding SNCA gene in PD) clearly suggest a primary involvement of the protein in neurodegeneration 3, 7, 8. In addition, recent data show that Lewy bodies are highly prevalent in the brains of individuals who have died in the course of disorders that are not normally classified as synucleinopathies, e.g., Alzheimer's disease 6. Such accumulations are unlikely to be simply coincidental; to delineate their role in the disease process and how they interact with tau and Aβ pathologies and microglial activation accurate in vivo biomarkers are needed.

This mini‐symposium consists of 4 chapters dealing with most aspects of α‐synuclein in the context of neurodegeneration. In Chapter 1, Berkhoudt Lassen and co‐workers describe interaction partners to α‐synuclein, which may either prevent or promote α‐synuclein misfolding and aggregation, likely depending on a stochastic process that initiates on a background of selective vulnerability 5,11. Chapter 2, by Emmanouilidou and Vekrellis, details normal α‐synuclein production, secretion and clearance, and how disrupted α‐synuclein homeostasis may initiate pathology spreading over the brain 12. Chapter 3 discusses the role of α‐synuclein aggregates in triggering inflammatory responses from microglia 13. Finally, Chapter 4 Atik and co‐workers give an updated account of the diagnostic utility of α‐synuclein detection and quantification in clinic ally accessible tissue specimens (biopsies from salivary glands and the gastrointestinal tract mucosa), as well as in biofluids, such as cerebrospinal fluid, plasma and saliva 14.

Altogether, the volume summarizes a large body of recent literature on the relevance of α‐synuclein as a diagnostic and prognostic biomarker, as well as a disease‐promoting agent when its normal homeostasis and important physiological functions are disrupted. The editors are to be congratulated for assembling a strong team with diverse expertise to give us a coherent picture of the current state of art in α‐synuclein‐focused research. The volume is to be read by both clinical researchers and those who are focused on basic research on neurodegeneration.