Centers for Molecular Medicine
Office: CMM 546
Lab: CMM 550/573
Office Phone: (631) 632-9664
Fax: (631) 632-6661
My research is committed to studying the complexity inherent in biological systems for the purpose of improving human health. My lab focus is on Amyotrophic Lateral Sclerosis and neurodegenerative diseases. I feel that model organisms are vital tools with which we can answer fundamental questions about biology and medicine, based in molecular genetics, cellular and organismal biology, and developmental/degenerative biology. My research broadly encompasses three areas with related research questions, as follows:
Theme #1: Nuclear Transport Defects in a Novel Form of Neurodegeneration.
We have identified both a mouse model in a novel gene where mutations result in defects in the nuclear pore complex and in nucleocytoplasmic transport.
- How do these mutations result in altered nuclear trafficking?
- What are the interactions of the mutant protein(s) with nuclear pore components?
- Do these alterations reflect an accelerated aging phenotype of motor neurons?
We are using mouse models, mammalian and human cell culture to study these genetic defects in the contect of nuclear transportation and neurodegeneration.
Theme #2: Impact of Genetics and Environmental Toxicants on ALS.
Environmental neurotoxicants have been implicated in the development of ALS, but how these interact with genetic susceptibilities is presently unknown.
- Do these toxins interact with the molecular pathways involved in genetic forms of ALS?
- How do these pathways correlate with age-dependent changes in gene expression, DNA methylation patterns and proteomic alterations?
Our hope is to determine biochemical pathways that intersect between the genetic and chemical insults to discover more about commonalities between these neurological disorders.
Theme#3: The Role of Retrotransposons in Neurodegeneration.
Retrotransposons are inherited virus-like entities that constitute approximately 40% of the human genome. When retrotransposons are active, they can replicate and reinsert into new chromosomal locations. This process is highly toxic, in part because it produces DNA damage that can lead to cell death. An emerging literature (including work from our SBU collaborator Joshua Dubnau) implicates retrotransposons in ALS.
- Are retrotransposons activated in mammalian models of ALS?
- What triggers (genetic or environmental) ALS protein pathology and retrotransposon activation.
Sayed-Zahid AA*, Sher RB* (*co-first Authors), Stacey RS, Anderson LC, Patenaude KE, Cox GA. 2019. Functional rescue of congenital muscular dystrophy with megaconial myopathy in a mouse model of the disease. Human Molecular Genetics. doi: 10.1093/hmg/ddz068.
Weatherly LM, Nelson AJ, Shim J, Riitano AM, Gerson ED, Hart AJ, de Juan-Sanz J, Ryan TA, Sher RB, Hess ST, Gosse JA. 2018. Antimicrobial Agent Triclosan Disrupts Mitochondrial Structure, Revealed by Super-resolution Microscopy, and Inhibits Mast Cell Signaling via Calcium Modulation. Toxicology and Applied Pharmacology 349: 39-54.
Sher RB. 2017. The Interaction Of Genetics And Environmental Toxicants In Amyotrophic Lateral Sclerosis: Results From Animal Models. Neural Regeneration Research 12(6): 903-906.
Powers S, Kwok S, Lovejoy E, Lavin T, Sher RB. 2017. Embryonic Exposure to the Environmental Neurotoxin BMAA Negatively Impacts Early Neuronal Development and Progression of Neurodegeneration in the Sod1-G93R Zebrafish Model of Amyotrophic Lateral Sclerosis. Toxicological Sciences 157(1): 129-140. **Editor’s Highlight**
Goody MF, Sher RB, Henry CA. 2015. Hanging On For The Ride: Adhesion To The Extracellular Matrix Mediates Cellular Responses In Skeletal Muscle Morphogenesis And Disease. Developmental Biology. 401(1):75-91.
Heiman-Patterson TD, Blankenhorn EP, Sher RB, Jiang J, Welsh P, Dixon MC, Jeffrey JI, Wong P, Cox GA, Alexander GM. 2015. Genetic Background Effects on Disease Onset and Lifespan of the Mutant Dynactin p150Glued Mouse Model of Motor Neuron Disease PLoS One. 10(3): e0117848
Sher RB*, Heiman-Patterson MD* (*co-first Authors), Blankenhorn EA, Jiang J, Alexander G, Deitch JS, Cox GA. 2014. A Major QTL on Mouse Chromosome 17 Resulting in Lifespan Variability in SOD1-G93A Transgenic Mouse Models of Amyotrophic Lateral Sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 15(7-8): 588-600.
Li Z, Wu G, Sher RB, Khavandgar Z, Hermansson M, Cox GA, Doschak MR, Murshed M, Beier F, Vance DE. 2014. Choline Kinase Beta is Required for Normal Endochondral Bone Formation. Biochim Biophys Acta (PMID:24637075).
Sher RB, Cox GA, Ackert-Bicknell C. 2012. Development and Disease of Mouse Muscular and Skeletal Systems. In “The Laboratory Mouse, Second Edition.” (HJ Hedrich. Ed.). Elsevier Inc., San Diego.
Sher, RB, Cox GA, Mills KD, Sundberg JP. 2011. Rhabdomyosarcomas in aging A/J mice. PLoS One. 6(8): e23498.
Mitsuhashi S, Hatakeyama H, Karahashi M, Koumura T, Nonaka I, Hayashi YK, Noguchi S, Sher RB, Nakagawa Y, Manfredi G, Goto Y, Cox GA, Nishino I. 2011. Muscle choline kinase beta defect causes mitochondrial dysfunction and increased mitophagy. Human Molecular Genetics 20(19): 3841-3851
Mitsuhashi S, Ohkuma A, Talim B, Karahashi M, Koumura T, Aoyama C, Kurihara M, Qunlivan R, Sewry C, Mitsuhashi H, Goto K, Koksai B, Kale G, Ikeda K, Taguchi R, Noguchi S, Hayashi YK, Nonaka I, Sher RB, Sugimoto H, Nakagawa Y, Cox GA, Topaloglu H, Nishino I. 2011. A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis. American Journal of Human Genetics. 12(2): 79-86.
Heimann-Patterson TD, Sher RB, Blankenhorn EA, Alexander G, Deitch JS, Kunst CB, Maragakis N, Cox G. 2011. Effect of Genetic Background on Phenotype Variability in Transgenic Mouse Models of Amyotrophic Lateral Sclerosis: A window of opportunity in the search for genetic modifiers. Amyotrophic Lateral Sclerosis 12(2): 79-86.
Wu G, Sher RB, Cox GA, Vance DE. 2010. Differential expression of choline kinase isoforms in skeletal muscle explains the phenotypic variability in the rostrocaudal muscular dystrophy mouse. Biochim Biophys Acta. 1801(4): 446-454
Wu G, Sher RB, Cox GA, Vance DE. 2009. Understanding the muscular dystrophy caused by deletion of choline kinase beta in mice. Biochim Biophys Acta. 1791(5): 347-356.
Sher RB, Aoyama C, Huebsch KA, Ji S, Kerner J, Yang Y, Frankel WN, Hoppel CL, Wood PA, Vance DE, Cox GA. 2006. A rostrocaudal muscular dystrophy caused by a defect in choline kinase beta, the first enzyme in phosphatidylcholine biosynthesis. Journal of Biological Chemistry 281(8): 4938-4948.
Huebsch KA, Kudryashova E, Wooley CM, Sher RB, Seburn KL, Spencer MJ, Cox GA. 2005. Mdm muscular dystrophy: interactions with calpain 3 and a novel functional role for titin’s n2a domain. Human Molecular Genetics 14(19): 2801-2811.
Wooley CM, Sher RB, Frankel WN, Cox GA, and Seaburn KL. 2005. Gait analysis detects early changes in transgenic SOD1(G93A) mice. Muscle Nerve 32: 43-50.