Research Focus
The focus of research in my laboratory is centered on CNS development, particularly with regard to the formation and maintenance of myelin. Myelin is the tightly compacted multilamellar sheath that surrounds axons and promotes saltatory conduction of nerve impulses. The myelin proteolipid protein gene (PLP1) encodes the most abundant protein found in mature myelin from the CNS. Expression of the gene is regulated spatiotemporally in oligodendrocytes, with peak expression occurring during the active myelination period of CNS development. PLP1 expression is tightly controlled. Misregulation of the gene in humans can result in the X-linked dysmyelinating disorder Pelizaeus-Merzbacher disease (PMD) or spastic paraplegia type 2 (SPG2). Transgenic mice carrying a null mutation or extra copies of the gene demonstrate a variety of conditions, from late-onset demyelination and axonopathy, to severe early-onset dysmyelination. With the use of transgenic and transfection paradigms, we have been able to show that the first intron of the PLP1 contains an enhancer region that is required for expression in oligodendrocytes, as well as in other cell types that express PLP1. This region abuts/overlaps a couple of recently discovered, alternatively spliced exons that are primarily restricted to the human species. Current efforts in the laboratory are focused on 1) identifying the transcription factors/architectural proteins that mediate enhancer function in PLP1 intron 1; 2) test whether critical mutations in the enhancer could be the cause of PMD/SPG2 in patients having a normal PLP1 coding sequence and the standard gene dosage; 3) elucidate the spatiotemporal expression and function of PLP1 splice variants that incorporate a ‘human-specific’ exon from what is classically defined as intron 1. We are also using our PLP1-lacZ transgenic mice as a tool to screen for small molecules that stimulate remyelination, as possible therapies for demyelinating diseases such as multiple sclerosis.
A separate project in the laboratory seeks to identify the genetic cause of mesenchymal phenotype that spontaneously arose in one of our mouse colonies.
Recent Publications
Hamdan H, Kockara NT, Jolly LA, Haun S, Wight PA (2015) Control of human PLP1expression through transcriptional regulatory elements and alternatively spliced exons in intron 1. ASN Neuro 7(1) pii: 1759091415569910. doi: 10.1177/1759091415569910. PMCID: PMC4342368
Wight PA (2017) Effects of intron 1 sequences on human PLP1 expression and their implications in PLP1-related disorders. ASN Neuro 9(4):1759091417720583. doi: 10.1177/1759091417720583. PMCID: PMC5528184
Hamdan H, Patyal P, Kockara NT, Wight PA (2018) The wmN1 enhancer region in intron 1 is required for expression of human PLP1. Glia 66(8):1763-1774. doi: 10.1002/glia.23339. PMCID: PMC6201313
Dobretsov M, Hayar A, Kockara NT, Kozhemyakin M, Light KE, Patyal P, Pierce D.R., Wight PA (2019) A transgenic mouse model to selectively identify a3 Na,K-ATPase expressing cells in the nervous system. Neuroscience 398:274-294. PMCID: PMC6331239
Hijazi H, Coelho FS, Gonzaga-Jauregui C, Bernardini L, Mar SS, Manning MA, Hanson-Kahn A, Naidu S, Srivastava S, Lee JA, Jones JR, Friez MJ, Alberico T, Torres B, Fang P, Cheung SW, Song X, Davis-Williams A, Jornlin C, Wight PA, Patyal P, Taube J, Poretti A, Inoue K, Zhang F, Pehlivan D, Carvalho CMB, Hobson GM, Lupski JR (2020) Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome. Hum. Mutat. 141:150-168. PMCID: PMC6953250
Patyal P, Kockara NT, Wight PA (2020) The wmN1 enhancer region of the mouse myelin proteolipid protein gene (mPlp1) is indispensable for expression of an mPlp1-lacZtransgene in both the CNS and PNS. Neurochem. Res. 45(3):663-671. PMCID: PMC7060809
Grant funding (2014 – present)
Current Funding
NIH – National Institute of Neurological Disorders and Strokes; R01 NS106179-01A; Principal Investigator: Patricia A. Wight (25% effort; 3 calendar months); Title: Elucidation of mechanisms controlling human and mouse myelin PLP1 gene expression; Total direct costs: $1,093,750 ($218,750 annually); Dates: 04/01/2019-03/31/2024
Gift from the Rampy Foundation for MS Research (~$25,000/year); Dates: 2012 – present
Past Funding
Development Enhancement for Proposals (DEAP) award, UAMS Research Committee; Principal Investigator: Patricia A. Wight; Title: Elucidation of mechanisms controlling human and mouse PLP1 gene expression; Total direct costs: $24,141.16; Dates: 10/12/18 – 04/11/20
National Multiple Sclerosis Society (NMSS) Research Grant RG 2705E5/2 (competitive renewal of RG 2705D4/1); Principal Investigator: Patricia A. Wight (25% effort); Title: Control of myelin proteolipid protein gene expression during development and remyelination; Total direct costs: $188,236; Dates: 10/01/12 – 09/30/13, no-cost extension to 09/30/14
Students/Postdocs
Graduate Students
Anna Dobretsova, Ph.D. student, 1995 – 2000
Current position: Operations Coordinator, Molecular Diagnostics Laboratory, Northside Hospital, Atlanta, GA
Shenyang Li, Ph.D. student, 1995 – 2001
Current position: Staff Scientist, Central Arkansas Veterans Healthcare System
Fanxue Meng, Ph.D. student, 1999 – 2006
Glauber Bruno Pereira, Ph.D. student, 2005 – 2010
Current position: Attending Physician in Pulmonary and Critical Care, Mercy Hospital Northwest Arkansas
Hamdan Hamdan, Ph.D. student, 2007 – 2012
Current position: Assistant Professor, AlFaisal University, Riyadh, Saudi Arabia
Pankaj Patyal, Ph.D. student, 2016 – present
Postdoctoral Fellows
Anna Dobretsova, Ph.D., 2000 – 2005
Current position: Operations Coordinator, Molecular Diagnostics Laboratory, Northside Hospital, Atlanta, GA
Olga E. Zolova, Ph.D., 2003 – 2006
Neriman Tuba Kockara, M.D./Ph.D., 2009 – 2016
Current position: Resident Physician (PGY1), Department of Psychiatry and Behavioral Sciences, McGovern Medical School, UTHealth, Houston, TX
Daniel Fil, Ph.D., 2020 – present
