LRP10 variants in progressive supranuclear palsy

Vergouw, Leonie J.M.; Melhem, Shamiram; Kaat, Laura Donker; Chiu, Wang Zheng; Kuipers, Demy J.S.; Breedveld, Guido J.; Wang, Li San; Naj, Adam C; Mlynarksi, Elizabeth; Cantwell, Laura B.; Quadri, Marialuisa; Ross, Owen A.; Dickson, Dennis W.; Schellenberg, Gerard D.; Swieten, John C. van; Bonifati, Vincenzo; Jong, Frank Jan de

doi:10.1016/j.neurobiolaging.2020.04.016

Cited by 8 publications

(8 citation statements)

References 31 publications

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“…The recently discovered pathogenic variants in LRP10 (low-density lipoprotein receptor-related protein 10) associated with autosomaldominant, inherited forms of PD, PD dementia (PDD) and DLB, further strengthen the evidence of the overlapping genetic bases in the Lewy body disorders (LBD) [70,86]. Moreover, the association of LRP10 variants with progressive supranuclear palsy (PSP) [87] and amyotrophic lateral sclerosis (ALS) [63], together with the data showing that LRP10 is a driver of a specific molecular subtype of Alzheimer's disease (AD) [62], provide evidence of potential mechanistic roles for LRP10 across a broader spectrum of neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 73%

LRP10 interacts with SORL1 in the intracellular vesicle trafficking pathway in non-neuronal brain cells and localises to Lewy bodies in Parkinson’s disease and dementia with Lewy bodies

et al. 2021

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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.

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Section: Introductionmentioning

confidence: 73%

LRP10 interacts with SORL1 in the intracellular vesicle trafficking pathway in non-neuronal brain cells and localises to Lewy bodies in Parkinson’s disease and dementia with Lewy bodies

et al. 2021

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“…This variant was also observed by us in one out of 645 controls who were not neurologically examined [5]. Last, the p.Gly326Asp variant has been previously reported in a pathologically con- firmed MSA patient [8], and found by us in a patient with clinically diagnosed PSP [14]. The lack of pathological examination in some of the previously reported patients complicates the overall interpretation of these findings.…”

Section: Discussionmentioning

confidence: 53%

“…Lastly, two Chinese and one Dutch cohort studies of sporadic and familial PD and DLB patients provided independent, albeit limited, additional evidence for an association of LRP10 variants with disease [11][12][13]. In addition, we recently found evidence for enrichment of rare, possibly pathogenic LRP10 variants in a large cohort of patients with progressive supranuclear palsy (PSP), mostly with a pathologically confirmed diagnosis [14]. In conclusion, despite some negative reports, additional evidence has been collected on a role for rare LRP10 variants in independent PD cohorts, and potentially other neurodegenerative diseases such as PSP.…”

Section: Introductionmentioning

confidence: 99%

Clinical and Pathological Phenotypes of LRP10 Variant Carriers with Dementia

Vergouw

Geut

Breedveld

et al. 2020

JAD

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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.

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“…In this study, two possibly pathogenic variants, p.Gly326Asp and p.Asp389Asp in two patients of the discovery cohort and seven possibly pathogenic variants, such as p.Arg158His, p.Cys220Tyr, p.Thr278Ala, p.Gly306Asp, p.Glu486Asp, p.Arg554*, and p.Arg661Cys in eight patients from the validation cohort were identified. 61 Mutations in the leucine-rich repeat kinase 2 ( LRRK2 ) gene have consistently been found to cause both familial and sporadic cases of PD. Impact of LRRK2 gene variations on the risk of PSP was explored in a few studies.…”

Section: Genetic Risk Factors Of Pspmentioning

confidence: 99%

Genetic and Epigenetic Constructs of Progressive Supranuclear Palsy

Debnath

Dey

Sreenivas

et al. 2022

Annals of Neurosciences

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Background: Progressive supranuclear palsy (PSP) is a rapidly progressive primary tauopathy characterized by vertical gaze palsy, postural instability, and mild dementia. PSP shows high clinical and pathologic heterogeneity. Although a few risk factors exist, such as advanced age and environmental toxins, the precise etiology remains largely elusive. Compelling evidence now suggests that genetic background plays a pivotal role in the pathogenetic pathways of PSP. Notably, PSP is genetically and phenotypically a complex disorder. Given the tau pathology, several studies in the past have identified microtubule-associated protein tau ( MAPT) gene mutations/variations and its haplotype as the major genetic risk factor of PSP, both in the sporadic and the familial forms. Subsequently, genome-wide association studies (GWAS) also identified several novel risk variants. However, these genetic risk determinants fail to explain the pathogenetic basis of PSP and its phenotypic spectrum in majority of the cases. Some genetic variants are known to confer the risk, while others seem to act as modifier genes. Summary: Besides the complex genetic basis of PSP, the pathobiological mechanisms, differential diagnosis, and management of patients with PSP have further been complicated by genetic conditions that mimic the phenotypes of PSP. This is now becoming increasingly apparent that interactions between genetic and environmental factors significantly contribute to PSP development. Further, the effect of environmental factors seems to be mediated through epigenetic modifications. Key message: Herein, we provide a comprehensive overview of the genetic and epigenetic constructs of PSP and highlight the relevance of genetic and epigenetic findings in the pathobiology of PSP.

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LRP10 variants in progressive supranuclear palsy

Cited by 8 publications

References 31 publications

LRP10 interacts with SORL1 in the intracellular vesicle trafficking pathway in non-neuronal brain cells and localises to Lewy bodies in Parkinson’s disease and dementia with Lewy bodies

LRP10 interacts with SORL1 in the intracellular vesicle trafficking pathway in non-neuronal brain cells and localises to Lewy bodies in Parkinson’s disease and dementia with Lewy bodies

Clinical and Pathological Phenotypes of LRP10 Variant Carriers with Dementia

Genetic and Epigenetic Constructs of Progressive Supranuclear Palsy

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