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Studies Of The Pigment-Type Switching Genes Atrn And Mgrn1: Evidence For A Defect In Endosomal/Lysosomal Protein Trafficking As A Cause Of Hyperpigmentation And Spongiform Neurodegeneration
Mice with mutations in the genes Attractin (Atrn) and Mahogunin ring finger-1 (Mgrn1) have remarkably similar phenotypes: null mutations at either locus cause both a hyperpigmented coat-color phenotype and a progressive spongiform neurodegeneration. This noteworthy phenotypic overlap suggests that ATRN and MGRN1 gene products work together to accomplish a conserved cellular process that is important for both pigmentation and the prevention of neurodegeneration. In the pigment cell, the function of ATRN and MGRN1 is known to be important for the downregulation of signaling by the master regulator of pigment production, the melanocortin 1 receptor (MC1R). Using the convenient model system of the pigment cell, I have determined that ATRN physically interacts with both MGRN1 and MC1R, and that ATRN displays a constitutive endolysosomal trafficking behavior that is MGRN1-dependent. I propose a model wherein the interaction between ATRN and MGRN1 localizes the ATRN/MC1R complex to the site of protein sorting by the Endosomal Sorting Complex Required for Transport (ESCRT) protein TSG101, which is a known MGRN1 interactor and a target of MGRN1's E3 ubiquitin ligase activity. This coordinated behavior of ATRN and MGRN1 may direct the sorting of ATRNassociated MC1R into the intracisternal vesicles of multivesicular bodies (MVBs) by ESCRT proteins, providing a novel mechanism for attenuation of MC1R signaling. If the pigment-type switching defects of Atrn and Mgrn1 mutants are caused by a defect in ESCRT activity, a similar failure of ESCRT sorting could underlie the spongiform neurodegeneration seen in these mutants, and perhaps in human spongiform encephalopathies such as prion disease and HIV-associated dementia. As a proof-of-concept experiment to test this hypothesis, I knocked out the ESCRT protein TSG101 in neurons of adult mice to determine whether ESCRT dysfunction can cause spongiform neurodegeneration. Here I present preliminary results suggesting a profound neurodegenerative consequence of ECSRT dysfunction. Keywords: attractin, mahogunin ring finger 1, melanocortin 1 receptor, ATRN, MGRN1, MC1R, pigment-type switching, spongiform neurodegeneration, spongiform change, spongiform encephalopathy, lysosomal targeting, lysosomal trafficking, multivesicular body sorting, TSG101, ESCRT, endogenous retrovirus, prion.
dissertation or thesis