A look at variant-specific boosters: The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) has raised the question of whether current COVID-19 vaccines protect against VOCs and if a variant specific vaccine may be needed. Of the currently identified VOCs, the Delta variant is believed to be the most transmissible, whereas the Beta variant appears to be the most vaccine resistant. Corbett et al . looked at the effect of vaccine boosting using either the original WA-1 strain vaccine or a Beta variant–specific booster. Around 6 months after the primary two-dose vaccine series, a third boost vaccination resulted in higher neutralizing antibody levels against VOCs in nonhuman primates. Regardless of whether the boost was from the original vaccine or the Beta-specific version, similar increases in neutralizing antibody levels were observed and resulted in enhanced viral protection. —PNK

Synucleinopathies are a set of devastating neurodegenerative diseases that share a pathologic accumulation of the protein α-synuclein (α-syn). This accumulation causes neuronal death resulting in irreversible dementia, deteriorating motor symptoms, and devastating cognitive decline. While the etiology of these conditions remains largely unknown, microglia, the resident immune cells of the central nervous system (CNS), have been consistently implicated in the pathogenesis of synucleinopathies. Microglia are generally believed to be neuroprotective in the early stages of α-syn accumulation and contribute to further neurodegeneration in chronic disease states. While the molecular mechanisms by which microglia achieve this role are still being investigated, here we highlight the major findings to date. In this review, we describe how structural varieties of inherently disordered α-syn result in varied microglial receptor-mediated interactions. We also summarize which microglial receptors enable cellular recognition and uptake of α-syn. Lastly, we review the downstream effects of α-syn processing within microglia, including spread to other brain regions resulting in neuroinflammation and neurodegeneration in chronic disease states. Understanding the mechanism of microglial interactions with α-syn is vital to conceptualizing molecular targets for novel therapeutic interventions. In addition, given the significant diversity in the pathophysiology of synucleinopathies, such molecular interactions are vital in gauging all potential pathways of neurodegeneration in the disease state.

Aggregation of misfolded α-synuclein (α-syn) is the major component of Lewy bodies and neurites in Parkinson’s disease (PD) and related α-synucleinopathies. Some α-syn mutations (e.g., A53T) in familial PD recapitulate the α-syn pathology in transgenic mice, which supports the importance of pathologic α-syn in driving the pathogenesis of α-synucleinopathies. Lymphocyte activation gene 3 (Lag3) is a receptor of α-syn fibrils facilitating pathologic α-syn spread; however, the role of Lag3 in mediating the pathogenesis in α-syn transgenic mice is not clear. Here, we report that depletion of Lag3 in human α-syn A53T transgenic (hA53T) mice significantly reduces the level of detergent-insoluble α-syn aggregates and phosphorylated ser129 α-syn, and inhibits activation of microglia and astrocytes. The absence of Lag3 significantly delays disease progression and reduces the behavioral deficits in hA53T transgenic mice leading to prolonged survival. Taken together, these results show that Lag3 contributes to the pathogenesis in the α-syn A53T transgenic mouse model.

Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid β precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson’s disease and related α-synucleinopathies.