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.
Highlights
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder affecting approximately 1–2% of the population above the age of 65 years [1]
Increased serum soluble LAG3 (sLAG3) levels were found to be associated with more severe non-motor symptoms as evaluated by non-motor symptoms scale (NMSS) scores, as well as excessive daytime sleepiness [7]. In this regard, increased cerebrospinal fluid (CSF) levels of YKL-40, an inflammatory marker, have been correlated with faster cognitive impairment in PD [38], and the concentration of tumor necrosis factor-α, interleukin-1β and nitric oxide in the CSF have been associated with probable REM sleep behavior disorder in PD patients [39]. These findings suggest that excessive inflammation may accompany non-motor symptoms of PD, and Lymphocyte-activation gene 3 (LAG3), as an indicator of cellular immune responses, may reflect the increased inflammation related to non-motor PD manifestations [7]
Clinical evidence has shown that serum and CSF sLAG3 may be associated with PD development and a clinical phenotype, suggesting that sLAG3 could represent an emerging PD biomarker
Summary
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder affecting approximately 1–2% of the population above the age of 65 years [1]. The key pathological hallmarks of the disease involve the intracellular accumulation of α-synuclein in the form of Lewy bodies and Lewy dendrites, as well as the dopaminergic neuronal loss in the substantia pars compacta (SNpc) resulting in nigrostriatal degeneration [1,2,3]. The D1 domain contains a unique extra loop and a small amino acid sequence that confers binding intracytoplasmic part [11]. LAG3 is highly expressed in peripheral immune organs including the spleen and the thymus, organs including the spleen and the thymus, and in the central nervous system (CNS) [13]. Given the implication of LAG3 in immune regulation, it may play an important role in the neuroinflammatory processes underlying the pathogenesis of PD, by affecting the cell-to-cell transmission of α-synuclein in a “prion-like” manner [16]. We discuss recent preclinical and clinical evidence on the role of LAG3 in PD
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