Role of LRP10 in Parkinson's disease in a Taiwanese cohort

Liao, Ting-Wei; Wang, Chun‐Chieh; Chung, Wen‐Hung; Su, Shih‐Chi; Chin, Szu-Han; Fung, Hon Chung; Wu, Yih‐Ru

doi:10.1016/j.parkreldis.2021.06.026

Cited by 3 publications

(1 citation statement)

References 30 publications

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“…These diseases are referred to as Lewy body diseases (LBDs), and they share pathological hallmarks that include degeneration of dopaminergic neurons in the substantia nigra pars compacta and other brain areas, and the presence of intra-neuronal α-synuclein-containing aggregates called Lewy bodies (Attems et al, 2021). After the initial report (Quadri et al, 2018), additional, rare LRP10 variants have been described in LBD patients (Chen et al, 2019; Gagliardi et al, 2021; Li et al, 2021; Liao et al, 2021; Manini et al, 2021; Neri et al, 2021; Periñán et al, 2020; Song et al, 2023; Tan et al, 2019; Vergouw et al, 2019; Zhao et al, 2021a; Zhao et al, 2020) and in a spectrum of neurodegenerative disorders including Alzheimer’s disease (AD) (Vergouw et al, 2020a), frontotemporal dementia (Daida et al, 2019), progressive supranuclear palsy (Vergouw et al, 2020b), and amyotrophic lateral sclerosis (Ni et al, 2021). In addition to these genetic findings, functional evidence associating LRP10 in processes relevant for neurodegenerative disorders has also been reported.…”

Section: Introductionmentioning

confidence: 99%

Interactome mapping reveals a role for LRP10 in autophagy and NDFIP1-mediated α-synuclein secretion

Mascaro,

Ferraro,

Boumeester

et al. 2023

Preprint

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Variants in theLRP10gene have been found in a spectrum of neurodegenerative disorders, including Lewy body diseases (LBDs). In brains of LBD patients, LRP10 is found in neuronal α-synuclein-containing Lewy bodies, astrocytes, and vasculature, but not in inclusion-free neurons. Furthermore, recent work suggests that LRP10 is involved in α-synuclein processing and transmission, which is disrupted by the LBD-associatedLRP10:c.1424+5G>A variant (LRP10-Splice). In spite of the cumulating genetic and functional evidence for a role of LRP10 in neurodegenerative disorders, our knowledge about the biological processes in which LRP10 is involved is incomplete. In this work, we provide a list of LRP10 interactors identified via LRP10 co-immunoprecipitation and mass spectrometry in LRP10-overexpressing cells and induced pluripotent stem cells (iPSC)-derived astrocytes. In addition to interactors and biological processes previously associated with LRP10, we identified novel interactors and pathways that may provide new insights into LRP10 function. Based on these findings, we focused on the involvement of LRP10 in the autophagy and unconventional secretion pathways via its interaction with the autophagy receptor SQSTM1/p62 and the ubiquitin-proteasome adaptor protein NDFIP1, respectively. We demonstrate that changes in LRP10 levels, either via knock-out or overexpression, affect p62 levels and autophagy in HuTu-80 cells and iPSC-derived astrocytes. Furthermore, we found that both LRP10 and NDFIP1 stimulate α-synuclein secretion and synergistically affect intracellular α-synuclein levels. Next, we studied the LRP10 interactome and related biological processes in iPSC-derived astrocytes carrying the LRP10-Splice variant. Although various interactors and biological processes were shared between wild-type LRP10 (LRP10-WT) and LRP10-Splice, others were only found in either LRP10-WT or LRP10-Splice. Interestingly, we found that LRP10-Splice responded differently to autophagy-modulating drugs in comparison to LRP10-WT. Furthermore, we show that LRP10-Splice interferes with the LRP10-WT:NDFIP1 interaction and NDFIP1-mediated α-synuclein secretion. Finally, we investigated the interactome of a secreted LRP10 species only found in conditioned media from LRP10-Splice carrier cells, and identify biological processes that might be impacted by the secreted LRP10-Splice specific protein. In summary, this study enhances our understanding of LRP10 biology, describes LRP10 functions in autophagy and NDFIP1-mediated α-synuclein secretion, and reveals potentially interesting differences between LRP10-WT and LRP10-Splice carrier cells that might be relevant to better understand the role of LRP10 in LBDs pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Interactome mapping reveals a role for LRP10 in autophagy and NDFIP1-mediated α-synuclein secretion

Mascaro,

Ferraro,

Boumeester

et al. 2023

Preprint

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Genetic analysis of the LRP10 gene in Chinese patients with Parkinson’s disease

et al. 2022

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Monogenic Parkinson’s Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing

Jia

Fellner

Kumar

2022

Genes

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Parkinson’s disease may be caused by a single pathogenic variant (monogenic) in 5–10% of cases, but investigation of these disorders provides valuable pathophysiological insights. In this review, we discuss each genetic form with a focus on genotype, phenotype, pathophysiology, and the geographic and ethnic distribution. Well-established Parkinson’s disease genes include autosomal dominant forms (SNCA, LRRK2, and VPS35) and autosomal recessive forms (PRKN, PINK1 and DJ1). Furthermore, mutations in the GBA gene are a key risk factor for Parkinson’s disease, and there have been major developments for X-linked dystonia parkinsonism. Moreover, atypical or complex parkinsonism may be due to mutations in genes such as ATP13A2, DCTN1, DNAJC6, FBXO7, PLA2G6, and SYNJ1. Furthermore, numerous genes have recently been implicated in Parkinson’s disease, such as CHCHD2, LRP10, TMEM230, UQCRC1, and VPS13C. Additionally, we discuss the role of heterozygous mutations in autosomal recessive genes, the effect of having mutations in two Parkinson’s disease genes, the outcome of deep brain stimulation, and the role of genetic testing. We highlight that monogenic Parkinson’s disease is influenced by ethnicity and geographical differences, reinforcing the need for global efforts to pool large numbers of patients and identify novel candidate genes.

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Role of LRP10 in Parkinson's disease in a Taiwanese cohort

Cited by 3 publications

References 30 publications

Interactome mapping reveals a role for LRP10 in autophagy and NDFIP1-mediated α-synuclein secretion

Interactome mapping reveals a role for LRP10 in autophagy and NDFIP1-mediated α-synuclein secretion

Genetic analysis of the LRP10 gene in Chinese patients with Parkinson’s disease

Monogenic Parkinson’s Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing

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