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The Genetics of REM Sleep Behavior Disorder and Its Conversion to Overt Neurodegeneration

出版	McGill University Libraries, 2022
URL	http://books.google.com.hk/books?id=ZG8WzwEACAAJ&hl=&source=gbs_api

註釋"REM sleep behavior disorder (RBD), characterized by dream-enactment behaviors, provides one of the strongest opportunities to improve neurodegenerative disease therapeutics. Researchers have linked RBD and the devastating conditions Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Deemed synucleinopathies, these three diseases have key similarities; pathology is characterized by accumulation of the protein alpha-synuclein in the brain, diagnosis occurs when significant brain damage has already spread, and there are currently no neuroprotective treatments available. RBD is a key to address the latter two points; an estimated 90% of RBD patients will develop overt neurodegeneration, most likely a synucleinopathy. RBD is thus an ideal population for early intervention. Understanding factors that affect RBD risk, pathology, and phenoconversion is critical for developing synucleinopathy neuroprotective treatments. Genetic studies play an important role in these aims. Great strides have been made particularly in PD genetics, where large-scale studies show potential druggable targets, causal factors for PD, and the importance of genetic stratification in clinical trials. RBD studies will improve upon these advancements by targeting a population earlier in synucleinopathy disease course, as well as a more specific group; the presence of RBD represents a more severe subtype of synucleinopathies associated with increased cognitive decline. Preliminary studies show genetic risk for RBD does not completely overlap with that of synucleinopathies. For example, a strong risk locus for PD, LRRK2, is not associated with increased RBD risk. In DLB, the current strongest genetic predictor, APOE, is similarly lacking association with RBD. These distinctions imply a unique genetic profile for RBD and underline the importance of characterizing RBD genetic risk on its own, which is the foundation for this thesis. I examine the role of synucleinopathy genetic loci in RBD through gene candidate studies, focusing on the autophagy lysosomal pathway (ALP), and then perform the first investigation of RBD risk on the genome-wide scale. Chapters 2-4 focus on gene candidate studies, investigating synucleinopathy risk loci and their role in RBD risk and conversion. In Chapter 2, I confirm that variants in GBA are a strong risk factor for RBD and may affect rate of conversion from RBD to overt synucleinopathy. Chapter 3 details an in-depth investigation of the PD GWAS risk locus TMEM175. I show its association with RBD risk and present evidence for potential pathological mechanisms. Chapter 4 investigates the locus that gives synucleinopathies their name: SNCA. This gene encodes the alpha-synuclein protein which is the primary component of Lewy bodies and hallmark of PD, DLB, and MSA pathology. I show that variants in the 5' region of SNCA are associated with dementia-related synucleinopathies while the 3' region is solely associated with PD. Chapter 5 details the first examination of RBD using genome-wide association study (GWAS). I performed a GWAS meta-analysis, replicating the previously identified RBD loci detailed in Chapters 2-4 and identifying two novel loci, INPP5F and SCARB2. Pathway analysis confirmed our hypothesis that the ALP plays an important role in RBD. The RBD polygenic risk score, which is a summation of one's genetic risk for RBD based on GWAS results, shows predictive power to differentiate between RBD cases and controls. I present potential functional mechanisms for phenotypic differences between RBD, DLB, and PD based on differing genetic risk variants and gene expression at SNCA and SCARB2, and show that RBD has a stronger genetic correlation with DLB than PD. This thesis confirms a distinct genetic component to RBD and lays important groundwork for future genetic contributions to clinical trial design, early detection, and treatment of synucleinopathies"--