NPC1 variants are not associated with Parkinson’s disease, REM-sleep behaviour disorder or Dementia with Lewy bodies in European cohorts

Alpha synucleinopathies are a group of neurodegenerative disorders characterized by alpha synuclein and Lewy body accumulation in the brain. These disorders include mainly Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and their prodromal rapid-eye-movement (REM)-sleep behavior disorder (RBD). Alpha synucleinopathies have complex etiology and may show overlap with other disorders. One such group of disorders is lysosomal storage disorders (LSDs), characterized by a lysosomal accumulation of undegraded substrates, often due to the dysfunction of various lysosomal enzymes (Filocamo and Morrone, 2011). Many commonalities have been observed in both groups, including alpha synuclein deposits in the brain, substantia nigra pathology, lysosomal dysfunction, lipid metabolism alterations, and impairment of the ubiquitin-proteasome system (Shachar et al., 2011). Additionally, a number of genes, including GBA, SMPD1, ASAH1 and GALC, have been identified as contributors to both alpha synucleinopathies and LSDs (Alcalay et al., 2019, Deane et al., 2011, Nalls et al., 2019, Riboldi and Di Fonzo, 2019, Robak et al., 2017).

Biallelic mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene lead to Niemann-Pick disease Types A and B, and heterozygous SMPD1 variants have been associated with PD and DLB (Alcalay et al., 2019, Clark et al., 2015, Desnick et al., 2010). The third class of Niemann-Pick disease, Type C (NPC), is caused by variants in the NPC intracellular cholesterol transporter 1 gene (NPC1). NPC has also been connected to synucleinopathies, as multiple NPC1 variant carriers have been reported to display PD symptoms and Lewy body deposits in the brain (Chiba et al., 2014, Josephs et al., 2004, Kluenemann et al., 2013; Schneider et al, 2019). A genetic study has attempted to examine the relationship between NPC1 variants and PD, finding no association (Ouled Amar Bencheikh et al., 2020). However, this study may have been underpowered and did not examine associations with other synucleinopathies.

In the present study we aimed to further elucidate the role of NPC1 in alpha synucleinopathies, by testing if common and rare variants in NPC1 were associated with PD, DLB and RBD in a total of 6,546 patients and 6,551 controls.

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