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

Angelopoulou, Efthalia; Paudel, Yam Nath; Clara, Villa; Shaikh, Mohd Farooq; Piperi, Christina

doi:10.3390/biology9040086

Cited by 21 publications

(18 citation statements)

References 75 publications

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“…In fact, a LAG-3 fused to an immunoglobulin module has been used as a potent vaccine adjuvant due to its potent capacity to cause full maturation of human monocyte-derived DC. Interestingly, LAG-3 has also been shown to be expressed in neurons, where it specifically binds to and co-endocytoses with pathologic α-synuclein [59][60][61].…”

Section: Cell and Tissue Expressionmentioning

confidence: 99%

“…Interestingly, LAG-3 has also been shown to be expressed in neurons, where it specifically binds to and co-endocytoses with pathologic α-synuclein [ 59 , 60 , 61 ].…”

Section: Regulation Of Lag-3 Expressionmentioning

confidence: 99%

“…Emerging preclinical and clinical evidence suggests that LAG-3 is associated with an increased risk of Parkinson’s disease (PD) [ 59 ]. LAG-3 is expressed in neurons and acts as a binding receptor for the pathologic fibrillary α-synuclein, mediating its aggregation, intracellular transmission, and spreading [ 60 ]. This process involves pre-formed α-synuclein fibrils followed by exogenous endocytosis by LAG-3 engagement on neurons [ 61 ].…”

Section: Lag-3 In Diseasementioning

confidence: 99%

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Understanding LAG-3 Signaling

Chocarro

Blanco

Zuazo

et al. 2021

IJMS

106

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Lymphocyte activation gene 3 (LAG-3) is a cell surface inhibitory receptor with multiple biological activities over T cell activation and effector functions. LAG-3 plays a regulatory role in immunity and emerged some time ago as an inhibitory immune checkpoint molecule comparable to PD-1 and CTLA-4 and a potential target for enhancing anti-cancer immune responses. LAG-3 is the third inhibitory receptor to be exploited in human anti-cancer immunotherapies, and it is considered a potential next-generation cancer immunotherapy target in human therapy, right next to PD-1 and CTLA-4. Unlike PD-1 and CTLA-4, the exact mechanisms of action of LAG-3 and its relationship with other immune checkpoint molecules remain poorly understood. This is partly caused by the presence of non-conventional signaling motifs in its intracellular domain that are different from other conventional immunoregulatory signaling motifs but with similar inhibitory activities. Here we summarize the current understanding of LAG-3 signaling and its role in LAG-3 functions, from its mechanisms of action to clinical applications.

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Section: Cell and Tissue Expressionmentioning

confidence: 99%

“…Interestingly, LAG-3 has also been shown to be expressed in neurons, where it specifically binds to and co-endocytoses with pathologic α-synuclein [ 59 , 60 , 61 ].…”

Section: Regulation Of Lag-3 Expressionmentioning

confidence: 99%

Section: Lag-3 In Diseasementioning

confidence: 99%

See 1 more Smart Citation

Understanding LAG-3 Signaling

Chocarro

Blanco

Zuazo

et al. 2021

IJMS

106

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“…Among three identified transmembrane protein candidates, LAG3 exhibited superior selectivity for binding to exogenous α-Syn PFFs in comparison with α-Syn monomers. The binding of α-Syn-biotin PFF to LAG3 led to α-Syn PFF endocytosis and neuronal transmission, spreading neurotoxicity [ 68 ].…”

Section: Novel Therapeutic Strategies In Pd Managementmentioning

confidence: 99%

Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update

2022

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Parkinson’s disease (PD) is a neurodegenerative disorder pathologically distinguished by degeneration of dopaminergic neurons in the substantia nigra pars compacta. Muscle rigidity, tremor, and bradykinesia are all clinical motor hallmarks of PD. Several pathways have been implicated in PD etiology, including mitochondrial dysfunction, impaired protein clearance, and neuroinflammation, but how these factors interact remains incompletely understood. Although many breakthroughs in PD therapy have been accomplished, there is currently no cure for PD, only trials to alleviate the related motor symptoms. To reduce or stop the clinical progression and mobility impairment, a disease-modifying approach that can directly target the etiology rather than offering symptomatic alleviation remains a major unmet clinical need in the management of PD. In this review, we briefly introduce current treatments and pathophysiology of PD. In addition, we address the novel innovative therapeutic targets for PD therapy, including α-synuclein, autophagy, neurodegeneration, neuroinflammation, and others. Several immunomodulatory approaches and stem cell research currently in clinical trials with PD patients are also discussed. Moreover, preclinical studies and clinical trials evaluating the efficacy of novel and repurposed therapeutic agents and their pragmatic applications with encouraging outcomes are summarized. Finally, molecular biomarkers under active investigation are presented as potentially valuable tools for early PD diagnosis.

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“…The neuropathological hallmarks of PD include the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of Lewy bodies and Lewy neurites mainly consisting of α-synuclein [ 9 , 10 ]. Although the etiology of PD remains obscure, mitochondrial dysfunction, abnormal α-synuclein aggregation, excessive neuroinflammation, lysosomal impairment and dysregulation of lipid metabolism contribute to its pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Arylsulfatase A (ASA) in Parkinson’s Disease: From Pathogenesis to Biomarker Potential

et al. 2020

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Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease, is a clinically heterogeneous disorder, with obscure etiology and no disease-modifying therapy to date. Currently, there is no available biomarker for PD endophenotypes or disease progression. Accumulating evidence suggests that mutations in genes related to lysosomal function or lysosomal storage disorders may affect the risk of PD development, such as GBA1 gene mutations. In this context, recent studies have revealed the emerging role of arylsulfatase A (ASA), a lysosomal hydrolase encoded by the ARSA gene causing metachromatic leukodystrophy (MLD) in PD pathogenesis. In particular, altered ASA levels have been detected during disease progression, and reduced enzymatic activity of ASA has been associated with an atypical PD clinical phenotype, including early cognitive impairment and essential-like tremor. Clinical evidence further reveals that specific ARSA gene variants may act as genetic modifiers in PD. Recent in vitro and in vivo studies indicate that ASA may function as a molecular chaperone interacting with α-synuclein (SNCA) in the cytoplasm, preventing its aggregation, secretion and cell-to-cell propagation. In this review, we summarize the results of recent preclinical and clinical studies on the role of ASA in PD, aiming to shed more light on the potential implication of ASA in PD pathogenesis and highlight its biomarker potential.

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

Cited by 21 publications

References 75 publications

Understanding LAG-3 Signaling

Understanding LAG-3 Signaling

Emerging Therapeutic Strategies for Parkinson’s Disease and Future Prospects: A 2021 Update

Arylsulfatase A (ASA) in Parkinson’s Disease: From Pathogenesis to Biomarker Potential

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