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Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by resting tremor, bradykinesia, muscle rigidity, and abnormal gait. The low-density lipoprotein receptor–related protein 10 (LRP10) was recently shown to be a causal gene for PD, and different ethnic cohorts have distinct frequencies and spectrum of LRP10 variants. Methods: We sequenced the full coding regions and exon–intron boundaries of LRP10 in 129 patients with sporadic Chinese PD to further investigate the connection of LRP10 with PD in a sample of Chinese patients. Results: In this study, we identified four potentially pathogenic mutations, including one novel mutation of p.Gly328Asp and three known mutations of p.Cys165Tyr, p.Arg230Trp, and p.Arg661His in four of the 129 Chinese patients with PD. Conclusion: According to our study, the LRP10 gene may attribute to PD pathogenesis. [ABSTRACT FROM AUTHOR]

We report on a patient with Parkinson's disease and dementia who underwent DBS with excellent response in motor features; the genotype is heterozygous for a novel LRP10 variant in trans with a GBA variant. He had a more severe phenotype compared to the father who only carries the LRP10 variant. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson's disease (PD) belongs to a family of neurodegenerative diseases characterized by alpha-synuclein accumulation in neurons, whose etiopathogenesis remains largely uncovered. Recently, LRP10 has been associated with PD, Parkinson's disease Dementia (PDD) and Dementia with Lewy Bodies (DLB) by linkage analysis and positional cloning in an Italian family with late-onset PD. After the first characterization of a LRP10 pathogenic variant, other eight mutations have been detected in an international series of 660 probands with either a clinical or pathological diagnosis of PD, PDD or DLB. However, the results of following replication studies were inconclusive and the pathogenic role of LRP10 is still debated. The aim of this study is to sequence the LRP10 gene in an Italian cohort of clinically-diagnosed PD patients and to compare the frequency of the identified variants with the ones found in a large cohort of Italian exomes.Methods: A cohort of 664 PD patients was analyzed by targeted Next Generation Sequencing approach. Identified LRP10 variants were subsequently confirmed by Sanger sequencing and searched for in an in-house database including 3596 Italian exomes.Results: We identified three PD patients carrying a rare heterozygous, potentially pathogenic variant (p.R296C, p.R549Q, p.R661C). None of them was detected in 3596 Italian exomes. Two of them (p.R296C and p.R661C) have been previously reported in one sporadic PD and one definite Progressive supranuclear palsy patients respectively. All three carriers had late-onset PD responsive to levodopa, characterized by both motor and non-motor features, but no cognitive impairment.Conclusion: We report three rare possibly-pathogenic LRP10 variants in PD patients from Italy. Further investigations are required to definitively establish their role in alpha-synucleinopathies. [ABSTRACT FROM AUTHOR]

Loss-of-function variants in the low-density lipoprotein receptor-related protein 10 (LRP10) gene have been associated with autosomal-dominant Parkinson's disease (PD), PD dementia, and dementia with Lewy bodies (DLB). Moreover, LRP10 variants have been found in individuals diagnosed with progressive supranuclear palsy and amyotrophic lateral sclerosis. Despite this genetic evidence, little is known about the expression and function of LRP10 protein in the human brain under physiological or pathological conditions. To better understand how LRP10 variants lead to neurodegeneration, we first performed an in-depth characterisation of LRP10 expression in post-mortem brains and human-induced pluripotent stem cell (iPSC)-derived astrocytes and neurons from control subjects. In adult human brain, LRP10 is mainly expressed in astrocytes and neurovasculature but undetectable in neurons. Similarly, LRP10 is highly expressed in iPSC-derived astrocytes but cannot be observed in iPSC-derived neurons. In astrocytes, LRP10 is present at trans-Golgi network, plasma membrane, retromer, and early endosomes. Interestingly, LRP10 also partially co-localises and interacts with sortilin-related receptor 1 (SORL1). Furthermore, although LRP10 expression and localisation in the substantia nigra of most idiopathic PD and DLB patients and LRP10 variant carriers diagnosed with PD or DLB appeared unchanged compared to control subjects, significantly enlarged LRP10-positive vesicles were detected in a patient carrying the LRP10 p.Arg235Cys variant. Last, LRP10 was detected in Lewy bodies (LB) at late maturation stages in brains from idiopathic PD and DLB patients and in LRP10 variant carriers. In conclusion, high LRP10 expression in non-neuronal cells and undetectable levels in neurons of control subjects indicate that LRP10-mediated pathogenicity is initiated via cell non-autonomous mechanisms, potentially involving the interaction of LRP10 with SORL1 in vesicle trafficking pathways. Together with the specific pattern of LRP10 incorporation into mature LBs, these data support an important mechanistic role for disturbed vesicle trafficking and loss of LRP10 function in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

LDL receptor-related protein (LRP) 10 was recently identified as a Parkinson's disease gene through genome-wide linkage and sequencing analysis, but its role in Parkinson's disease in various populations is still unclear. The aim of this study was to determine the frequency and spectrum of LRP10 mutations in a cohort of Parkinson's disease patients from mainland China. All LRP10 exons and their flanking intron regions were screened by direct sequencing in 567 unrelated Parkinson's disease patients and 600 unrelated controls. We detected 29 exonic or splicing variants in 79 patients with Parkinson's disease. Five variants (c.A181C:p.I61L, c.C652T:p.Q218X, c.C833T:p.T278I, c.T1592G:p.I531S, c.T1697C:p.L566P) were predicted to be disease-causing or damaging by multiple in silico tools. Our study provides genetic evidence that LRP10 defects may correlate with sporadic Parkinson's disease. [ABSTRACT FROM AUTHOR]

Recently, the LRP10 gene has been associated with Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and dementia with Lewy bodies (DLB). The aim of the present study was to evaluate the presence of mutations of the LRP10 gene in patients with PD or DLB from Southern Italy. Sequencing analysis revealed only 2 missense and 3 synonymous variants in patients and control subjects and a rare variant p.L622F in a PD case. These results suggest that LRP10 mutations are not a frequent cause of PD and DLB in Southern Italy. [ABSTRACT FROM AUTHOR]

Background: Rare variants in the low-density lipoprotein receptor related protein 10 gene (LRP10) have recently been implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB).Objective: We searched for LRP10 variants in a new series of brain donors with dementia and Lewy pathology (LP) at autopsy, or dementia and parkinsonism without LP but with various other neurodegenerative pathologies.Methods: Sanger sequencing of LRP10 was performed in 233 donors collected by the Netherlands Brain Bank.Results: Rare, possibly pathogenic heterozygous LRP10 variants were present in three patients: p.Gly453Ser in a patient with mixed Alzheimer's disease (AD)/Lewy body disease (LBD), p.Arg151Cys in a DLB patient, and p.Gly326Asp in an AD patient without LP. All three patients had a positive family history for dementia or PD.Conclusion: Rare LRP10 variants are present in some patients with dementia and different brain pathologies including DLB, mixed AD/LBD, and AD. These findings suggest a role for LRP10 across a broad neurodegenerative spectrum. [ABSTRACT FROM AUTHOR]

Background: Recently, the LRP10 gene has been identified as a novel genetic cause in individuals affected by Parkinson's disease (PD), Parkinson's disease dementia, or dementia with Lewy bodies.Objective: We investigated the involvement of LRP10 mutations in Chinese patients with familial PD and reviewed previous studies of LRP10 mutations in patients with PD.Methods: A mutation analysis of the LRP10 gene was performed in a cohort of 205 unrelated Chinese patients with familial PD. Burden analysis was conducted using data from the Genome Aggregation Database and 5 genetic studies of LRP10 in patients with PD (including our cohort).Results: A total of 3 novel potentially pathogenic variants, c.32T>A (p.L11H), c.1184G>A (p.R395H), and c.1333G>A (p.A445T), were detected in 3 probands of our cohort. However, burden analysis argued against an overrepresentation of variant alleles in patients with PD.Conclusions: Genetic screening of the LRP10 gene in our cohort may provide independent, albeit limited, evidence for the pathogenicity of LRP10 in familial PD. Burden analysis using data from current studies failed to support the association between LRP10 and PD in general. Thus, more robust replication studies are warranted to determine the involvement of LRP10 in the pathogenesis of PD. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The phosphatase of regenerating liver (PRL) family, including PRL-1, PRL-2, and PRL-3, comprises protein tyrosine phosphatases whose deregulation is associated with the tumorigenesis and metastasis of many types of cancer. However, the underlying mechanism is poorly understood. In this study, aiming to increase understanding of the molecular mechanisms underlying the functions of PRL-1 and PRL-3, a yeast two-hybrid system was employed to screen for their interacting proteins. Alignment with the NCBI BLAST database revealed 12 interactive proteins: Synaptic nuclear envelope protein 2, emerin, mannose 6-phosphate receptor-binding protein 1, low-density lipoprotein receptor-related protein 10, Rab acceptor 1, tumor protein D52-like 2, selectin P ligand (SELPLG), guanylate binding protein 1, transmembrane and ubiquitin-like domain-containing 2, NADH:ubiquinone oxidoreductase subunit B8, syndecan 4 and FK506-binding protein 8 (FKBP8). These proteins are associated with cell proliferation, apoptosis, immune response, cell fate specification and metabolic process in biological process categories, and involved in various signaling pathways, including Alzheimer's disease, Parkinson's disease, Huntington's disease, hypertrophic cardiomyopathy and cell adhesion molecules. Interactions of PRL-1 with the prey proteins SELPLG and FKBP8 were confirmed by immunoprecipitation or immunostaining. Furthermore, SELPLG and FKBP8 suppressed PRL-1- or PRL-3-mediated p53 activity. Identification of the proteins interacting with PRL family proteins may provide valuable information to better understand the mechanism of PRL-mediated signal transduction in cancer and other diverse diseases. [ABSTRACT FROM AUTHOR]

Loss-of-function (LoF) variants in the low-density lipoprotein receptor-related protein 10 gene ( LRP10 ) have been recently implicated in the development of neurodegenerative diseases, including Parkinson's disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB). However, despite the genetic evidence, little is known about the LRP10 protein function in health and disease. Here, we describe a detailed protocol to efficiently generate a LRP10 LoF model in two independent LRP10-expressing cell lines, HuTu-80 and HEK 293T, using the CRISPR/Cas9 genome-editing tool. Our method efficiently generates bi-allelic LRP10 knockout (KO), which can be further utilized to elucidate the physiological LRP10 protein function and to model some aspects of neurodegenerative disorders. Graphical abstract: CRISPR/Cas9 workflow for the generation of the LRP10 KO. (1) Designed single guide RNA (sgRNA) is cloned into CRISPR/Cas9 px458 plasmid. (2) Cells are transfected with the CRISPR/Cas9 plasmid containing sgRNA. (3) Two days post transfection, cells are dissociated and sorted as single cells by fluorescence-activated cell sorting (FACS). (4) After several weeks, expanded clonal lines are (5) verified with Sanger sequencing for the presence of INDELs ( in sertions or del etions), RT-qPCR for the amounts of LRP10 mRNA transcript, and Western blotting for the analysis of the LRP10 protein levels., Competing Interests: Competing interests The authors declare no conflicts of interest or competing interests., (Copyright © 2022 The Authors; exclusive licensee Bio-protocol LLC.)

Abstract: Wnt signaling pathways play fundamental roles in the differentiation, proliferation and functions of many cells as well as developmental, growth, and homeostatic processes in animals. Low-density lipoprotein receptor (LDLR)-related protein (LRP) 5 and LRP6 serve as coreceptors of Wnt proteins together with Frizzled receptors, triggering activation of canonical Wnt/β-catenin signaling. Here, we found that LRP10, a new member of the LDLR gene family, inhibits the canonical Wnt/β-catenin signaling pathway. The β-catenin/T cell factor (TCF) transcriptional activity in HEK293 cells was activated by transfection with Wnt3a or LRP6, which was then inhibited by co-transfection with LRP10. Deletion of the extracellular domain of LRP10 negated its inhibitory effect. The inhibitory effect of LRP10 was consistently conserved in HEK293 cells even when GSK3β phosphorylation was inhibited by incubation with lithium chloride and co-transfection with constitutively active S33Y-mutated β-catenin. Nuclear β-catenin accumulation was unaffected by LRP10. The present studies suggest that LRP10 may interfere with the formation of the β-catenin/TCF complex and/or its binding to target DNA in the nucleus, and that the extracellular domain of LRP10 is critical for inhibition of the canonical Wnt/β-catenin signaling pathway. [Copyright &y& Elsevier]

Abstract: We report the characterization of a new member of the low-density lipoprotein receptor (LDLR) gene family designated LRP10. Human LRP10 cDNA encodes a 1905 amino acid type I membrane protein consisting of five functional domains characteristic of the LDLR gene family. CHO-ldlA7 cells transfected with human LRP10 cDNA bound LDLR-associated protein, but not β-VLDL and HDL. Human LRP10 transcripts were primarily found in the brain, muscle and heart. In situ hybridization of the rat brain showed that the transcripts were intensely present in the cerebral cortex, hippocampus, choroid plexus, ependyma and granular layer. In the developing rat brain, transcript levels gradually increased from postnatal day 1 to 20. Immunofluorescence analysis indicated that LRP10 was observed in the ventricular zone of the embryonic day 14.5 mouse cerebral cortex. The present studies suggest that LRP10 may play a significant role in the brain physiology other than lipoprotein metabolism. [Copyright &y& Elsevier]

Recently, LRP10 has been identified as a causative gene for Parkinson's disease (PD). However, subsequent studies showed inconsistent conclusions. To explore its relevance to PD, we systematically analyzed LRP10 rare mutations in a large Han Chinese familial PD cohort of 385 unrelated probands using segregation analysis, transcriptional effect analysis, and burden test. As a result, 3 missense variants and 1 splicing region variant in LRP10 were identified in 4 probands. Segregation analysis revealed 1 variant p.Arg66His cosegregating with PD status, 1 variant p.Ala613Ser not, and the other variant p.Gln581His unknown. The variant c.406+5G>T located at the splicing region has no effect on splicing, suggesting it is likely a rare neutral intronic variant. The burden test suggested no significant over-representation of rare variants in PD probands. Therefore, more robust independent studies are warranted to explore the pathogenicity of LRP10 mutations. • LRP10 mutation analysis in a large Han Chinese familial PD cohort. • Four novel rare variants in LRP10 were identified. • In this study, burden test does not support the pathogenicity of LRP10 variants for PD. [ABSTRACT FROM AUTHOR]

Low-density lipoprotein receptor-related protein 10 (LRP10) is associated with a series of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease which share genetic risk factors and pathophysiological processes with amyotrophic lateral sclerosis (ALS). To investigate whether LRP10 variants could cause a predisposition to ALS, we screened rare, pathogenic LRP10 variants among a cohort of 584 patients with ALS from mainland China and performed burden analysis using data from a large external database. A total of 7 rare, pathogenic variants in LRP10 , of which one (c.1182A>T, p.R394S) was novel, were identified in 11 unrelated patients. Burden analysis revealed significant associations between ALS and LRP10 at both the gene and single-variant levels (c.1721G>A, p.R574Q; c.1182A>T, p.R394S; and c.1681C>T, p.R561C). Interestingly, patients with sporadic ALS carrying variant c.1721G>A tended to have a bulbar onset, increased phenotype severity, and a worse prognosis. Our findings first provide independent evidence that rare, pathogenic LRP10 variants may be risk factors for ALS and delineate a special phenotype in patients with sporadic ALS carrying variant c.1721G>A. • For the first time, LRP10 variations are described in patients with amyotrophic lateral sclerosis (ALS) from mainland China. • Rare, pathogenic variants in LRP10 may be risk factors for ALS. • Patients with sporadic ALS carrying variant c.1721G>A tend to have a special phenotype. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore whether variants in LRP10 , recently associated with Parkinson's disease and dementia with Lewy bodies, are observed in 2 large cohorts (discovery and validation cohort) of patients with progressive supranuclear palsy (PSP). A total of 950 patients with PSP were enrolled: 246 patients with PSP (n = 85 possible (35%), n = 128 probable (52%), n = 33 definite (13%)) in the discovery cohort and 704 patients with definite PSP in the validation cohort. Sanger sequencing of all LRP10 exons and exon-intron boundaries was performed in the discovery cohort, and whole-exome sequencing was performed in the validation cohort. Two patients from the discovery cohort and 8 patients from the validation cohort carried a rare, heterozygous, and possibly pathogenic LRP10 variant (p.Gly326Asp, p.Asp389Asn, and p.Arg158His, p.Cys220Tyr, p.Thr278Ala, p.Gly306Asp, p.Glu486Asp, p.Arg554∗, p.Arg661Cys). In conclusion, possibly pathogenic LRP10 variants occur in a small fraction of patients with PSP and may be overrepresented in these patients compared with controls. This suggests that possibly pathogenic LRP10 variants may play a role in the development of PSP. • Exploration of LRP10 variants in progressive supranuclear palsy (PSP). • Ten of 950 patients were carriers of a possibly pathogenic LRP10 variant. • First study to show that LRP10 variants occur in a small fraction of patients with PSP. • LRP10 variants may be overrepresented in patients with PSP compared with controls. • LRP10 variants may play a role in the development of PSP. [ABSTRACT FROM AUTHOR]

Lipoprotein receptor-related protein 10 (LRP10) has been proposed as a novel causative gene for autosomal dominant Parkinson's disease (PD), and the c.919T>A (p.Tyr307Asn) variant has been identified as possibly involved in the development of familial PD and PD with dementia. We screened for the p.Tyr307Asn variant in a southern Spain population of 679 PD patients, of who 129 were familial cases, and 1217 unrelated healthy controls. A total of 3 carriers of the LRP10 p.Tyr307Asn variant were identified: 1 PD patient and 2 healthy controls. Together with the absence of a family history of PD, this finding might suggest a low penetrance variant as well as a limited role for p.Tyr307Asn in PD in our cohort. Nevertheless, a family history of Alzheimer's disease in the LRP10 p.Tyr307Asn carriers provides evidence for a possible association with dementia. • LRP10 gene has been recently associated with PD, PDD and DLB. • One PD patient and two healthy controls carried the previously reported LRP10 p.Tyr307Asn variant. • There was no family history of PD among the LRP10 p.Tyr307Asn carriers. • These findings suggest a limited role of LRP10 p.Tyr307Asn in PD. • A family history of AD in LRP10 p.Tyr307Asn carriers provides evidence for a possible association with dementia. [ABSTRACT FROM AUTHOR]

Mutations of the gene encoding low-density lipoprotein receptor–related protein 10 (LRP10) were recently detected in patients (heterogeneous races) with autosomal dominant inheritance of familial Parkinson's disease. The patients with Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies whose brain pathology indicated deposit of alpha-synuclein along with the co-occurrence of tau pathology and amyloid-beta plaques presented LRP10 mutations. LRP10 is localized in the vesicular structures and trans-Golgi network; its alteration leads to alpha-synuclein aggregation. Thus, we conducted the genetic screening of LRP10 among 187 patients with familial Parkinson's disease and 19 patients with atypical parkinsonian disorders, including frontotemporal dementia, progressive supranuclear palsy, and corticobasal syndrome. There were no putative pathogenic variants among patients with Parkinson's disease. We detected one rare variant, p.D198N, in a patient with frontotemporal dementia, without a cosegregation study. Overall, our findings showed that LRP10 variants are not causative for disease in our cohort. • We screened all exons of LRP10 for 187 patients including familial PD. • We included 19 patients with atypical parkinsonism diagnosed clinically. • No specific variants were found to be associated with familial PD. • A rare variant, p.D198N, was detected in a patient with frontotemporal dementia. • LRP10 variants have less evidence of causality for PD in our cohort. [ABSTRACT FROM AUTHOR]