|
Title
|
|
|
|
Monogenic and oligogenic mutations of the mitochondrial-lysosomal pathway are associated with Lewy body diseases
| |
|
Author
|
|
|
|
| |
|
Abstract
|
|
|
|
| Abstract Lewy body diseases (LBD) are a heterogeneous group of neurodegenerative brain diseases characterized by the presence of Lewy bodies and Lewy neurites, mainly composed of aggregated ?-synuclein, in neurons. Two disorders with substantial clinical, pathological and etiological overlap are at the two-side extremes of the LBD continuum: dementia with Lewy bodies (DLB) and Parkinson’s disease (PD). Although inherited LBD is rare with an estimated frequency of 5–15%, the identification of causal and risk genes have been instrumental in dissecting disease etiologies. A large part of the genetic etiology of LBD remains unexplained and the identification of novel genes will be instrumental in further unravelling the molecular basis and disease processes underlying LBD. This PhD project aimed to gain more insights in the molecular basis of LBDs using next generation sequencing based gene identification strategies combined with molecular cell biology approaches. Using whole exome sequencing in unrelated early-onset PD patients, we identified compound heterozygous mutations in ATP10B increasing risk for PD and functionally characterized ATP10B as a late endo-/lysosomal glucosylceramide and phosphatidylcholine lipid flippase, involved in lysosomal functionality and neuroprotection. Both ATP10B and the well-known LBD risk factor GBA play essential roles in the fate of lysosomal glucosylceramide, and dysfunction of both results in intra-lysosomal accumulation of glucosylceramide and lysosomal dysfunction. Additionally, using whole genome sequencing in two siblings affected with autosomal recessive early-onset DLB, we identified compound heterozygous mutations in VPS13C, which encodes a late endo-/lysosomal protein involved in glycerolipid transport. Our genetic and expression data suggest that in addition to previously identified premature termination codon mutations identified in PD patients also missense mutations in VPS13C can contribute to the risk of LBD by loss-of-function. Moreover, genetic profiling of the PD cohort for seven major genes associated with PD, including ATP10B and VPS13C, identified oligogenic variants in 4.76% of patients, suggesting more complex inheritance patterns of PD with oligogenic mutations of interconnected PD pathways. Whole exome sequencing of 172 PD patients implicated a possible role for lysosomal storage disorder gene variants in PD pathogenesis. Our results support the importance of lipid homeostasis alterations and lysosomal dysfunction in LBD pathogenesis, thereby opening new avenues for therapeutic intervention. The observation of more complex inheritance patterns and oligogenic mutations in patients highlights the crosstalk between interconnected PD pathways. In diagnostics, the presence of a monogenic pathogenic mutation should not serve as exclusion criteria to screen for other genetic variation. |
| |
|
Language
|
|
|
|
English
| |
|
Publication
|
|
|
|
Antwerp
:
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences
,
2020
| |
|
Volume/pages
|
|
|
|
234 p.
| |
|
Note
|
|
|
|
:
Van Broeckhoven, Christine [Supervisor]
| |
|