Towards identifying genetic modifiers of Fragile X-Associated Tremor/Ataxia Syndrome Open Access

Seong, Hwanwook (Spring 2022)

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The fragile X mental retardation 1 (FMR1) gene encodes the fragile X mental retardation protein (FMRP), which is vital for neuronal plasticity and the construction of neural networks. Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder that is characterized by complications in movement and cognition affecting premutation carriers (55-200 CGG repeats) of the FMR1 gene. Expanded CGG repeat RNA has been shown to play key roles in FXTAS pathogenesis. There is little insight into the modulation of metabolic pathways in relation to FXTAS. Exploring the changes in these mechanisms can pave new avenues for identifying effective biomarkers and understanding the pathogenesis of the disease. Lysosomes are organelles containing digestive enzymes necessary for cellular degradation, cell signaling, and metabolism. Deficient genes encoding lysosomal proteins can lead to lysosomal storage diseases (LSDs), which can lead to the buildup of toxic cellular materials. To identify the role of lysosome enzymes in FXTAS, this study analyzed a list of LSD-associated genes to genetically screen them for modifying the neuronal toxicity associated with CGG repeats in FXTAS models. The screen identified 11 candidate genes to express at least 60% enhancement in modulating CGG repeat toxicity. Of the 11 candidate genes, PEX12, GALNS, and GNS identify phytanic acid peroxisomal oxidation degradation and glycosaminoglycan degradation to be significantly dysregulated pathways. The knockdown of PEX12 resulted in elevated levels of 2-oxoglutarate and pristanate in modulating the phytanic acid peroxisomal oxidation pathway. Knockdown of GALNS identified N-acetyl galactosamine to be significantly downregulated in chondroitin sulfate degradation while knockdown of GNS identified 6-Deoxy-L-galactose and D-galactose significantly downregulated in keratan sulfate degradation. These results indicate the potential causal role of PEX12, GALNS, and GNS in FXTAS pathogenesis uncovering further understanding of how these genes can act as genetic modifiers of FXTAS. This study aims to analyze how various biochemical pathways in the lysosome and peroxisome can provide insight into the genetic relationship of LSD-associated genes with CGG repeat neurotoxicity in FXTAS.

Table of Contents

Introduction 1-3

Materials and methods 3-5

Results 5-17

i.    33 LSD-associated genes selected for observing metabolic perturbations in presence of r(CGG)90 5

ii.    Drosophila genetic screening identifies 11 candidate genes that exhibit significant enhancement with FXTAS CGG repeat toxicity 10-11

iii.    Branched-Chain Fatty Acid Catabolism may be perturbed in FXTAS: knockdown of Pex12 (PEX12) results in enhancement of CGG repeat toxicity 12-13

iv.    Glycosaminoglycan (GAG) degradation pathways may be involved in FXTAS pathogenesis: knockdown of GALNS and GNS result in enhancement of the CGG toxicity 16-17

Discussion 17-20

References 21-22

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