The neurodegenerative diseases ? Alzheimer?s Disease (AD), Parkinson?s Disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and others ? together constitute one of the most significant unmet challenges in human health, affecting greater than 50 million people worldwide with no treatments to slow or stop progression. With the advent of the genomewide association study (GWAS) in 2005, and the subsequent identification of hundreds of common variant risk factors for AD, PD, FTD, and ALS, we have many loci that may translate into new targets for therapeutic intervention. To date, however, few mechanistic studies have been performed as follow-up to these GWAS-generated leads. One exception to this general rule has been with respect to the 7p21 locus we and others reported in 2010 to confer risk for the AD-related dementia FTD. In the first five years of this R01, we used a combination of computational and bench-based approaches to definitively establish the expression quantitative trait locus (eQTL) relationship between GWAS-identified single nucleotide polymorphisms (SNPs) and expression of the target gene TMEM106B. We furthermore defined the causal genetic variant at this locus, its CTCF-based mechanism for altering expression of TMEM106B, and the deleterious effects on lysosomal pathways of altering TMEM106B expression. We coupled these mechanistic experiments with investigations of the genetic modifier effects of TMEM106B genotype in FTD due to C9orf72 hexanucleotide expansions. Thus, through our work and the work of others, the field has gained an understanding of the pathways through which genetic risk at 7p21 is conferred, and the groups of patients in which targeting of TMEM106B may be viable therapeutically. In this RO1 renewal application, we propose to deepen our understanding of TMEM106B biology, investigating its influence in multiple neurodegenerative diseases, and elucidating its role in lysosomal function and cellular health.
Specific Aim 1 : Determine whether genetic modifier effects of the GWAS-identified FTD common variant risk factor TMEM106B extend across a spectrum of neurodegenerative diseases. We will investigate TMEM106B genotype effects in >1300 longitudinally-followed AD, PD, FTD, and ALS patients. We will determine whether TMEM106B acts as a genetic modifier in PD associated with GBA mutations.
Specific Aim 2 : Elucidate the mechanisms by which changes in TMEM106B expression affect lysosomal- autophagy pathway function and cellular health. We will follow-up preliminary work demonstrating that TMEM106B may affect autophagosome-lysosome fusion through a VAMP8-Syntaxin17 pathway. We will investigate TMEM106B-induced changes in lysosomal acidification through direct measurement of ion conductances across the lysosomal membrane and investigations of TMEM106B?s role in assembly of the vacuolar ATPase.
Many genetic risk factors have been found for the various neurodegenerative diseases, but few of them have been functionally characterized in a way that is likely to lead to therapies for the millions of people who suffer from Alzheimer?s Disease, Parkinson?s Disease, Frontotemporal Dementia, and Amyotrophic Lateral Sclerosis. We seek here to understand how one genetic risk factor, TMEM106B, confers risk for neuronal loss, through lysosomal pathways that may affect a spectrum of neurodegenerative diseases.
| Jain, Nimansha; Chen-Plotkin, Alice S (2018) Genetic Modifiers in Neurodegeneration. Curr Genet Med Rep 6:11-19 |
| Chen-Plotkin, Alice S (2018) Parkinson disease: Blood transcriptomics for Parkinson disease? Nat Rev Neurol 14:5-6 |
| Tropea, Thomas F; Chen-Plotkin, Alice S (2018) Unlocking the mystery of biomarkers: A brief introduction, challenges and opportunities in Parkinson Disease. Parkinsonism Relat Disord 46 Suppl 1:S15-S18 |
| Chen-Plotkin, Alice S; Zetterberg, Henrik (2018) Updating Our Definitions of Parkinson's Disease for a Molecular Age. J Parkinsons Dis 8:S53-S57 |
| Gallagher, Michael D; Chen-Plotkin, Alice S (2018) The Post-GWAS Era: From Association to Function. Am J Hum Genet 102:717-730 |
| Deck, Benjamin L; Rick, Jacqueline; Xie, Sharon X et al. (2017) Statins and Cognition in Parkinson's Disease. J Parkinsons Dis 7:661-667 |
| Gallagher, Michael D; Posavi, Marijan; Huang, Peng et al. (2017) A Dementia-Associated Risk Variant near TMEM106B Alters Chromatin Architecture and Gene Expression. Am J Hum Genet 101:643-663 |
| Espay, Alberto J; Schwarzschild, Michael A; Tanner, Caroline M et al. (2017) Biomarker-driven phenotyping in Parkinson's disease: A translational missing link in disease-modifying clinical trials. Mov Disord 32:319-324 |
| Rosenthal, Liana S; Drake, Daniel; Alcalay, Roy N et al. (2016) The NINDS Parkinson's disease biomarkers program. Mov Disord 31:915-23 |
| Busch, Johanna I; Unger, Travis L; Jain, Nimansha et al. (2016) Increased expression of the frontotemporal dementia risk factor TMEM106B causes C9orf72-dependent alterations in lysosomes. Hum Mol Genet 25:2681-2697 |
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