Apolipoprotein E Genotype Contributes to Motor Progression in Parkinson's Disease

Pu, Jiali; Jin, Chong‐Yao; Wang, Zhong-Xuan; Fang, Yi; Li, Yaolin; Xue, Nai‐Jia; Zheng, Ran; Lin, Zhi‐Hao; Yan, Yiqun; Su, Xiaoli; Chen, Ying; Liu, Yi; Song, Zhe; Yan, Yaping; Tian, Jun; Yin, Xinzhen; Zhang, Baorong

doi:10.1002/mds.28805

Cited by 23 publications

(20 citation statements)

References 37 publications

(55 reference statements)

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“…In PD, APOE has been associated with age at onset, 16 cognition and dementia, and potentially motor progression, 17 but not PD risk. 1,18 In the GWAS of PD age at onset, the effect of APOE was shown to be similar between age at onset in cases and age of entry of controls.…”

Section: Discussionmentioning

confidence: 98%

“…APOE is the strongest genetic risk factor for AD, 10,14 and is also associated with cardiovascular disease (including coronary heart disease / coronary artery disease), and cholesterol levels. 15 In PD, APOE has been associated with age at onset, 16 cognition and dementia, and potentially motor progression, 17 but not PD risk. 1,18 In the GWAS of PD age at onset, the effect of APOE was shown to be similar between age at onset in cases and age of entry of controls.…”

Section: Apoementioning

confidence: 99%

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Genome-wide determinants of mortality and motor progression in Parkinson’s disease

Tan

Lawton

Pollard

et al. 2022

Preprint

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Background: There are 90 genetic risk variants for Parkinson's disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. Methods: We studied 6,766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out a genome wide survival study for time to motor progression, defined by reaching Hoehn and Yahr stage 3 or greater, cognitive impairment as defined by serial cognitive examination, and death (mortality). Findings: There was a robust effect of the APOE ϵ4 allele on mortality and cognitive impairment in PD. We identified three novel loci for mortality and motor progression, and nominated genes based on physical proximity or expression quantitative trait loci data. One locus within the TBXAS1 gene encoding thromboxane A synthase 1 was associated with mortality in PD (HR = 2.04 [95% CI 1.63 to 2.56], p-value = 7.71 x 10-10). Another locus near the SYT10 gene encoding synaptotagmin 10 was associated with mortality just above genome-wide significance (HR=1.36 [95% CI 1.21 to 1.51], p-value=5.31x10-8). A genomic variant associated with the expression of ADORA2A, encoding the A2A adenosine receptor, was associated with motor progression (HR=4.83 [95% CI 2.89 to 8.08], p-value=1.94x10-9). Only the non-Gaucher disease causing GBA PD risk variant E326K, of the known PD risk variants, was associated with progression in PD. Interpretation: We report three novel loci associated with PD progression or mortality. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, thromboxane synthesis, vesicular peptidergic neurotransmitter release and the A2A adenosine receptor may represent new candidates for disease modification in PD.

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Section: Discussionmentioning

confidence: 98%

Section: Apoementioning

confidence: 99%

Genome-wide determinants of mortality and motor progression in Parkinson’s disease

Tan

Lawton

Pollard

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…The ε4 allele of the APOE gene (APOE4) is a strong genetic risk factor for Lewy body dementia (LBD) [52,53]. APOE4 has also been implicated in the progression of cognitive impairment or motor dysfunction within PD [54][55][56][57][58][59][60][61]. Recently, we reported that the presence of APOE4 gene allele exacerbates α-Syn seeding in a large AD cohort and a small cohort of LBD cases [62].…”

Section: Discussionmentioning

confidence: 99%

LRP1 is a neuronal receptor for α-synuclein uptake and spread

Chen

Martens

Meneses

et al. 2022

Mol Neurodegeneration

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Background The aggregation and spread of α-synuclein (α-Syn) protein and related neuronal toxicity are the key pathological features of Parkinson’s disease (PD) and Lewy body dementia (LBD). Studies have shown that pathological species of α-Syn and tau can spread in a prion-like manner between neurons, although these two proteins have distinct pathological roles and contribute to different neurodegenerative diseases. It is reported that the low-density lipoprotein receptor-related protein 1 (LRP1) regulates the spread of tau proteins; however, the molecular regulatory mechanisms of α-Syn uptake and spread, and whether it is also regulated by LRP1, remain poorly understood. Methods We established LRP1 knockout (LRP1-KO) human induced pluripotent stem cells (iPSCs) isogenic lines using a CRISPR/Cas9 strategy and generated iPSC-derived neurons (iPSNs) to test the role of LRP1 in α-Syn uptake. We treated the iPSNs with fluorescently labeled α-Syn protein and measured the internalization of α-Syn using flow cytometry. Three forms of α-Syn species were tested: monomers, oligomers, and pre-formed fibrils (PFFs). To examine whether the lysine residues of α-Syn are involved in LRP1-mediated uptake, we capped the amines of lysines on α-Syn with sulfo-NHS acetate and then measured the internalization. We also tested whether the N-terminus of α-Syn is critical for LRP1-mediated internalization. Lastly, we investigated the role of Lrp1 in regulating α-Syn spread with a neuronal Lrp1 conditional knockout (Lrp1-nKO) mouse model. We generated adeno-associated viruses (AAVs) that allowed for distinguishing the α-Syn expression versus spread and injected them into the hippocampus of six-month-old Lrp1-nKO mice and the littermate wild type (WT) controls. The spread of α-Syn was evaluated three months after the injection. Results We found that the uptake of both monomeric and oligomeric α-Syn was significantly reduced in iPSNs with LRP1-KO compared with the WT controls. The uptake of α-Syn PFFs was also inhibited in LRP1-KO iPSNs, albeit to a much lesser extent compared to α-Syn monomers and oligomers. The blocking of lysine residues on α-Syn effectively decreased the uptake of α-Syn in iPSNs and the N-terminus of α-Syn was critical for LRP1-mediated α-Syn uptake. Finally, in the Lrp1-nKO mice, the spread of α-Syn was significantly reduced compared with the WT littermates. Conclusions We identified LRP1 as a key regulator of α-Syn neuronal uptake, as well as an important mediator of α-Syn spread in the brain. This study provides new knowledge on the physiological and pathological role of LRP1 in α-Syn trafficking and pathology, offering insight for the treatment of synucleinopathies.

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“…Genetically, patients with LBD had a higher risk of developing parkinsonism, and the PD genetic risk score was associated with an earlier age at onset (AAO) of LBD [1]. In addition, variants of APOE have been suggested to be associated with rapid progression of motor functions and dementia in PD [2,3], and BIN1 rs13403026 was shown to delay the AAO of GBA-associated PD [4]. Considering that GBA, TMEM175, and SNCA are risk genes for both LBD and PD, it is noteworthy to investigate whether BIN1 and APOE are also associated with the risk of PD.…”

Section: Enrichment Of Rare Variants Of Bin1 But Not Apoe Genes In Ch...mentioning

confidence: 99%

Enrichment of rare variants of BIN1 but not APOE genes in Chinese patients with Parkinson's disease

Chen

et al. 2022

J Intern Med

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Apolipoprotein E Genotype Contributes to Motor Progression in Parkinson's Disease

Cited by 23 publications

References 37 publications

Genome-wide determinants of mortality and motor progression in Parkinson’s disease

Genome-wide determinants of mortality and motor progression in Parkinson’s disease

LRP1 is a neuronal receptor for α-synuclein uptake and spread

Enrichment of rare variants of BIN1 but not APOE genes in Chinese patients with Parkinson's disease

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