Pathological Functions of LRRK2 in Parkinson’s Disease

Jeong, Ga Ram; Lee, Byoung Dae

doi:10.3390/cells9122565

Cited by 67 publications

(58 citation statements)

References 153 publications

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“…Furthermore, studies using PD-derived induced neuronal stem cells show that the loss of LRRK2 decreased the aggregation of the rogue protein [92]. This endorses the assertion that mutation of the gene LRRK2 is a risk factor for both the sporadic and familial form of PD [91].…”

Section: Genetic and α-Synuclein-related Pathological Processes In Pdmentioning

confidence: 53%

“…This allows for the rapid and effective propagation of α-synuclein as demonstrated in primary human brain pericytes obtained from post-mortem PD brains [ 90 ]. Interestingly, the LRRK2 gene has been implicated in both the aggregation and propagation of α-synuclein [ 91 ]. Furthermore, studies using PD-derived induced neuronal stem cells show that the loss of LRRK2 decreased the aggregation of the rogue protein [ 92 ].…”

Section: Risk Factors For Pdmentioning

confidence: 99%

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The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

Sian-Hülsmann

Riederer

2021

Cells

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The risk of Parkinson’s disease increases with age. However, the etiology of the illness remains obscure. It appears highly likely that the neurodegenerative processes involve an array of elements that influence each other. In addition, genetic, endogenous, or exogenous toxins need to be considered as viable partners to the cellular degeneration. There is compelling evidence that indicate the key involvement of modified α-synuclein (Lewy bodies) at the very core of the pathogenesis of the disease. The accumulation of misfolded α-synuclein may be a consequence of some genetic defect or/and a failure of the protein clearance system. Importantly, α-synuclein pathology appears to be a common denominator for many cellular deleterious events such as oxidative stress, mitochondrial dysfunction, dopamine synaptic dysregulation, iron dyshomeostasis, and neuroinflammation. These factors probably employ a common apoptotic/or autophagic route in the final stages to execute cell death. The misfolded α-synuclein inclusions skillfully trigger or navigate these processes and thus amplify the dopamine neuron fatalities. Although the process of neuroinflammation may represent a secondary event, nevertheless, it executes a fundamental role in neurodegeneration. Some viral infections produce parkinsonism and exhibit similar characteristic neuropathological changes such as a modest brain dopamine deficit and α-synuclein pathology. Thus, viral infections may heighten the risk of developing PD. Alternatively, α-synuclein pathology may induce a dysfunctional immune system. Thus, sporadic Parkinson’s disease is caused by multifactorial trigger factors and metabolic disturbances, which need to be considered for the development of potential drugs in the disorder.

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Section: Genetic and α-Synuclein-related Pathological Processes In Pdmentioning

confidence: 53%

Section: Risk Factors For Pdmentioning

confidence: 99%

The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

Sian-Hülsmann

Riederer

2021

Cells

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“…Mutations in the LRRK2 gene can cause autosomal dominant PD [ 73 ]. In certain ethnic groups, LRRK2 mutations have been estimated to be present in up to 40% of familial PD and 10% of sporadic PD cases [ 74 , 75 , 76 , 77 ]. The most common LRRK2 mutation, p.G2019S has been reported in many ethnic backgrounds and is estimated to account for 4% of familial PD and 1% of sporadic PD cases [ 13 , 74 , 78 ].…”

Section: Aging Lrrk2 and Pdmentioning

confidence: 99%

LRRK2 at the Crossroad of Aging and Parkinson’s Disease

Hur

Lee

2021

Genes

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Parkinson’s disease (PD) is a heterogeneous neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the widespread occurrence of proteinaceous inclusions known as Lewy bodies and Lewy neurites. The etiology of PD is still far from clear, but aging has been considered as the highest risk factor influencing the clinical presentations and the progression of PD. Accumulating evidence suggests that aging and PD induce common changes in multiple cellular functions, including redox imbalance, mitochondria dysfunction, and impaired proteostasis. Age-dependent deteriorations in cellular dysfunction may predispose individuals to PD, and cellular damages caused by genetic and/or environmental risk factors of PD may be exaggerated by aging. Mutations in the LRRK2 gene cause late-onset, autosomal dominant PD and comprise the most common genetic causes of both familial and sporadic PD. LRRK2-linked PD patients show clinical and pathological features indistinguishable from idiopathic PD patients. Here, we review cellular dysfunctions shared by aging and PD-associated LRRK2 mutations and discuss how the interplay between the two might play a role in PD pathologies.

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“…APOE is a well-established AD risk factor (62) with an important role in normal brain function (63) and the APOE e4 allele has been associated with cognitive decline in PD (10,64,65). LRRK2 is also occupying a central node in the protein network: LRRK2 has a dual role as a PD risk factor and a gene involved in PD pathogenesis (66,67) and encodes a protein kinase involved in autophagy. SNCA also occupies a central node in the PPI and is a key player in PD pathogenesis (68).…”

Section: Protein-protein Interaction Network Analysismentioning

confidence: 99%

Variable Effects of PD-Risk Associated SNPs and Variants in Parkinsonism-Associated Genes on Disease Phenotype in a Community-Based Cohort

et al. 2021

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Genetic risk factors for Parkinson's disease (PD) risk and progression have been identified from genome-wide association studies (GWAS), as well as studies of familial forms of PD, implicating common variants at more than 90 loci and pathogenic or likely pathogenic variants at 16 loci. With the goal of understanding whether genetic variants at these PD-risk loci/genes differentially contribute to individual clinical phenotypic characteristics of PD, we used structured clinical documentation tools within the electronic medical record in an effort to provide a standardized and detailed clinical phenotypic characterization at the point of care in a cohort of 856 PD patients. We analyzed common SNPs identified in previous GWAS studies, as well as low-frequency and rare variants at parkinsonism-associated genes in the MDSgene database for their association with individual clinical characteristics and test scores at baseline assessment in our community-based PD patient cohort: age at onset, disease duration, Unified Parkinson's Disease Rating Scale I-VI, cognitive status, initial and baseline motor and non-motor symptoms, complications of levodopa therapy, comorbidities and family history of neurological disease with one or more than one affected family members. We find that in most cases an individual common PD-risk SNP identified in GWAS is associated with only a single clinical feature or test score, while gene-level tests assessing low-frequency and rare variants reveal genes associated in either a unique or partially overlapping manner with the different clinical features and test scores. Protein-protein interaction network analysis of the identified genes reveals that while some of these genes are members of already identified protein networks others are not. These findings indicate that genetic risk factors for PD differentially affect the phenotypic presentation and that genes associated with PD risk are also differentially associated with individual disease phenotypic characteristics at baseline. These findings raise the intriguing possibility that different SNPs/gene effects impact discrete phenotypic characteristics. Furthermore, they support the hypothesis that different gene and protein-protein interaction networks that underlie PD risk, the PD phenotype, and the neurodegenerative process leading to the disease phenotype, and point to the significance of the genetic background on disease phenotype.

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Pathological Functions of LRRK2 in Parkinson’s Disease

Cited by 67 publications

References 153 publications

The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

The Nigral Coup in Parkinson’s Disease by α-Synuclein and Its Associated Rebels

LRRK2 at the Crossroad of Aging and Parkinson’s Disease

Variable Effects of PD-Risk Associated SNPs and Variants in Parkinsonism-Associated Genes on Disease Phenotype in a Community-Based Cohort

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