Lymphocyte-Activation Gene 3 (LAG3) Protein as a Possible Therapeutic Target for Parkinson's Disease: Molecular Mechanisms Connecting Neuroinflammation to α-Synuclein Spreading Pathology

Abstract

Parkinson's disease (PD) is the most common neurodegenerative movement disorder without any objective biomarker available to date. Increasing evidence highlights the critical role of neuroinflammation, including T cell responses, and spreading of aggregated α-synuclein in PD progression. Lymphocyte-activation gene 3 (LAG3) belongs to the immunoglobulin (Ig) superfamily expressed by peripheral immune cells, microglia and neurons and plays a key role in T cell regulation. The role of LAG3 has been extensively investigated in several human cancers, whereas until recently, the role of LAG3 in the central nervous system (CNS) has been largely unknown. Accumulating evidence highlights the potential role of LAG3 in PD pathogenesis, mainly by binding to α-synuclein fibrils and affecting its endocytosis and intercellular transmission, which sheds more light on the connection between immune dysregulation and α-synuclein spreading pathology. Serum and cerebrospinal fluid (CSF) soluble LAG3 (sLAG3) levels have been demonstrated to be potentially associated with PD development and clinical phenotype, suggesting that sLAG3 could represent an emerging PD biomarker. Specific single nucleotide polymorphisms (SNPs) of the LAG3 gene have been also related to PD occurrence especially in the female population, enlightening the pathophysiological background of gender-related PD clinical differences. Given also the ongoing clinical trials investigating various LAG3-targeting strategies in human diseases, new opportunities are being developed for PD treatment research. In this review, we discuss recent preclinical and clinical evidence on the role of LAG3 in PD pathogenesis and biomarker potential, aiming to elucidate its underlying molecular mechanisms.

Keywords: LAG3; Parkinson’s disease; biomarker; neuroinflammation; α-synuclein.

Figure 1

The structure of LAG3 and its cleaved soluble form (sLAG3). LAG3 is a transmembrane protein consisting of 498 amino acids, with four extracellular Ig-like domains (D1–D4) and an intracellular domain, containing an ‘EP’ (glutamic acid-proline) repeat responsible for anchorage and a KIEELE motif, which is required for the LAG3-mediated negative inhibitory signal. LAG-3 can be cleaved within the transmembrane domain at the connecting peptide (CP) by two members of metalloproteases known as ADAM 10 and ADAM 17 to release sLAG-3, which contributes to the regulatory function of LAG-3.

Figure 2

The role of LAG3 in the pathogenesis of Parkinson’s disease and its biomarker potential. LAG3 can bind to α-synuclein and trigger its endocytosis, contributing to α-synuclein cell-to-cell transmission. Overexpression of LAG3 may enhance the phosphorylation of α-synuclein at serine 129. LAG3 has been also implicated in α-synuclein dopaminergic neuronal loss, neurotoxicity and synaptic dysfunction. Clinical evidence has shown that soluble LAG3 (sLAG3) levels may be higher in patients with PD compared to controls (CTs) or patients with essential tremor (ET), whereas there is also evidence indicating that serum sLAG3 levels display no difference between PD patients and CTs. Lower sLAG3 levels in the cerebrospinal fluid (CSF) have been associated with PD development, and LAG3 gene expression has been also correlated with regional atrophy in magnetic resonance imaging (MRI) brain scans of patients with PD.