LRP10 interacts with SORL1 in the intracellular vesicle trafficking pathway in non-neuronal brain cells and localises to Lewy bodies in Parkinson\u2019s disease and dementia with Lewy bodies

Martyna M Grochowska,Wilma D J Van De Berg,Wiggert A Van Cappellen,Ana Carreras Mascaro,Valerie Boumeester,Domenico Natale,Vincenzo Bonifati,Anneke J A Kievit,Agnita J W Boon,Wim Mandemakers,Hanneke Geut,Netherlands Brain Bank ,Piero Parchi,Pietro Cortelli,Guido J Breedveld,Esther Sammler,Dario R Alessi

doi:10.1007/s00401-021-02313-3

Abstract

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.

Highlights

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are common neurodegenerative disorders strongly affecting the ageing population worldwide [27, Extended author information available on the last page of the article85]
We show that both lipoprotein receptor-related protein 10 (LRP10)-NT and LRP10-CT antibodies are able to interact with endogenous LRP10 protein expressed in HEK293T cells under non-denaturing and non-reducing conditions demonstrated by immunoprecipitation of LRP10 protein at the expected LRP10 molecular weight that was absent in LRP10 KO HEK293T cells (Fig. 1d)
Both LRP10-NT and LRP10-CT antibodies were validated by immunofluorescence in wild-type (WT) HuTu 80 cells, showing a vesiclelike staining pattern, which was absent in HuTu 80 LRP10KO cells (Fig. 1e)

Summary

Introduction

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are common neurodegenerative disorders strongly affecting the ageing population worldwide [27, Extended author information available on the last page of the article85]. Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are common neurodegenerative disorders strongly affecting the ageing population worldwide [27, Extended author information available on the last page of the article. Cardinal motor features of PD include bradykinesia, rigidity and rest tremor [12, 69]. These motor signs are usually preceded by non-motor manifestations such as olfactory dysfunction, rapid eye movement (REM) sleep behaviour disorder, depression, and constipation [12, 69]. DLB is clinically defined by a gradual cognitive decline as the initial manifestation, followed by parkinsonism in over 85% of. PD and DLB differ in the temporal sequence of prominent clinical symptoms, both are neuropathologically characterised by neuronal loss and the formation of intracellular α-synuclein-containing inclusions in surviving neurons, termed Lewy bodies (LB) and Lewy neurites (LN) [31]

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Results

Conclusion