The Double-Faceted Role of Leucine-Rich Repeat Kinase 2 in the Immunopathogenesis of Parkinson’s Disease

Zhang, Mengfei; Li, Chaoyi; Ren, Jie; Wang, Huakun; Fang, Yi; Wu, Junjiao; Tang, Yu

doi:10.3389/fnagi.2022.909303

Cited by 7 publications

(7 citation statements)

References 142 publications

(169 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Parkinson's disease-associated LRRK2 mutations enhance neuroinflammatory responses, increasing dopaminergic neuron loss and motor deficits. Experiments have shown that the knockdown of the LRRK2 gene in LRRK2 (R1441G) transgenic mice inhibits the conversion of microglia to a proinflammatory phenotype (Magistrelli et al, 2022;Zhang et al, 2022). Microglia-specific regulatory chromatin regions regulate LRRK2 expression in the human frontal cortex and substantiate these results in a human-induced pluripotent stem cell-derived microglia model (Langston et al, 2022).…”

Section: Microglia and Parkinson's Diseasementioning

confidence: 77%

New insight on microglia activation in neurodegenerative diseases and therapeutics

Xu,

Gao,

Sun

et al. 2023

Front. Neurosci.

View full text Add to dashboard Cite

Microglia are immune cells within the central nervous system (CNS) closely linked to brain health and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In response to changes in the surrounding environment, microglia activate and change their state and function. Several factors, example for circadian rhythm disruption and the development of neurodegenerative diseases, influence microglia activation. In this review, we explore microglia’s function and the associated neural mechanisms. We elucidate that circadian rhythms are essential factors influencing microglia activation and function. Circadian rhythm disruption affects microglia activation and, consequently, neurodegenerative diseases. In addition, we found that abnormal microglia activation is a common feature of neurodegenerative diseases and an essential factor of disease development. Here we highlight the importance of microglia activation in neurodegenerative diseases. Targeting microglia for neurodegenerative disease treatment is a promising direction. We introduce the progress of methods targeting microglia for the treatment of neurodegenerative diseases and summarize the progress of drugs developed with microglia as targets, hoping to provide new ideas for treating neurodegenerative diseases.

show abstract

Section: Microglia and Parkinson's Diseasementioning

confidence: 77%

New insight on microglia activation in neurodegenerative diseases and therapeutics

Xu,

Gao,

Sun

et al. 2023

Front. Neurosci.

View full text Add to dashboard Cite

show abstract

“…In addition, the relationship between LRRK2, another important PD-related protein, and autophagy and neuroinflammation has been extensively studied. We can learn more about the relationship between LRRK2 and microglial autophagy from a recently published review ( Zhang et al, 2022 ).…”

Section: Microglia Recognize Pathogens By Pattern Recognition Receptorsmentioning

confidence: 99%

Microglial autophagy in Alzheimer’s disease and Parkinson’s disease

Wang

et al. 2023

Front. Aging Neurosci.

View full text Add to dashboard Cite

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases, characterized by gradual and selective loss of neurons in the central nervous system. They affect more than 50 million people worldwide, and their incidence increases with age. Although most cases of AD and PD are sporadic, some are caused by genetic mutations that are inherited. Both sporadic and familial cases display complex neuropathology and represent the most perplexing neurological disorders. Because of the undefined pathogenesis and complex clinical manifestations, there is still no effective treatment for both AD and PD. Understanding the pathogenesis of these important neurodegenerative diseases is important for developing successful therapies. Increasing evidence suggests that microglial autophagy is associated with the pathogenesis of AD and PD, and its dysfunction has been implicated in disease progression. In this review, we focus on the autophagy function in microglia and its dysfunction in AD and PD disease models in an attempt to help our understanding of the pathogenesis and identifying new therapeutic targets of AD and PD.

show abstract

“…Large numbers of microglia expressing human leucocyte antigen (HLA)-DR have been detected in the brain of PD patients, particularly in areas of maximal neurodegeneration ( 15 , 17 ). Leucine-rich repeat kinase 2 ( LRRK2 ), a risk gene of PD, is highly expressed in microglia, monocytes and other immune cells ( 18 ), and has been reported to be associated with an increasing risk of Crohn’s disease, an inflammatory bowel disease and other autoimmune diseases ( 19 – 21 ). Alpha-synuclein specific T cell reactivity is associated with HLA-DRB1*15:01 and -DRB5*01:01 ( 22 , 23 ), and with preclinical and early PD ( 24 , 25 ), and the infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of PD ( 15 , 26 ).…”

Section: Introductionmentioning

confidence: 99%

Regulatory SVA retrotransposons and classical HLA genotyped-transcripts associated with Parkinson’s disease

Kulski,

Suzuki,

Shiina

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

IntroductionParkinson’s disease (PD) is a neurodegenerative and polygenic disorder characterised by the progressive loss of neural dopamine and onset of movement disorders. We previously described eight SINE-VNTR-Alu (SVA) retrotransposon-insertion-polymorphisms (RIPs) located and expressed within the Human Leucocyte Antigen (HLA) genomic region of chromosome 6 that modulate the differential co-expression of 71 different genes including the HLA classical class I and class II genes in a Parkinson’s Progression Markers Initiative (PPMI) cohort.Aims and methodsIn the present study, we (1) reanalysed the PPMI genomic and transcriptomic sequencing data obtained from whole blood of 1521 individuals (867 cases and 654 controls) to infer the genotypes of the transcripts expressed by eight classical HLA class I and class II genes as well as DRA and the DRB3/4/5 haplotypes, and (2) examined the statistical differences between three different PD subgroups (cases) and healthy controls (HC) for the HLA and SVA transcribed genotypes and inferred haplotypes.ResultsSignificant differences for 57 expressed HLA alleles (21 HLA class I and 36 HLA class II alleles) up to the three-field resolution and four of eight expressed SVA were detected at p<0.05 by the Fisher’s exact test within one or other of three different PD subgroups (750 individuals with PD, 57 prodromes, 60 individuals who had scans without evidence of dopamine deficits [SWEDD]), when compared against a group of 654 HCs within the PPMI cohort and when not corrected by the Bonferroni test for multiple comparisons. Fourteen of 20 significant alleles were unique to the PD-HC comparison, whereas 31 of the 57 alleles overlapped between two or more different subgroup comparisons. Only the expressed HLA-DRA*01:01:01 and -DQA1*03:01:01 protective alleles (PD v HC), the -DQA1*03:03:01 risk (HC v Prodrome) or protective allele (PD v Prodrome), the -DRA*01:01:02 and -DRB4*01:03:02 risk alleles (SWEDD v HC), and the NR_SVA_381 present genotype (PD v HC) at a 5% homozygous insertion frequency near HLA-DPA1, were significant (Pc<0.1) after Bonferroni corrections. The homologous NR_SVA_381 insertion significantly decreased the transcription levels of HLA-DPA1 and HLA-DPB1 in the PPMI cohort and its presence as a homozygous genotype is a risk factor (Pc=0.012) for PD. The most frequent NR_SVA_381 insertion haplotype in the PPMI cohort was NR_SVA_381/DPA1*02/DPB1*01 (3.7%). Although HLA C*07/B*07/DRB5*01/DRB1*15/DQB1*06 was the most frequent HLA 5-loci phased-haplotype (n, 76) in the PPMI cohort, the NR_SVA_381 insertion was present in only six of them (8%).ConclusionsThese data suggest that expressed SVA and HLA gene alleles in circulating white blood cells are coordinated differentially in the regulation of immune responses and the long-term onset and progression of PD, the mechanisms of which have yet to be elucidated.

show abstract

The Double-Faceted Role of Leucine-Rich Repeat Kinase 2 in the Immunopathogenesis of Parkinson’s Disease

Cited by 7 publications

References 142 publications

New insight on microglia activation in neurodegenerative diseases and therapeutics

New insight on microglia activation in neurodegenerative diseases and therapeutics

Microglial autophagy in Alzheimer’s disease and Parkinson’s disease

Regulatory SVA retrotransposons and classical HLA genotyped-transcripts associated with Parkinson’s disease

Contact Info

Product

Resources

About