Research Profile

Paul Young

Biography

Paul Young received his undergraduate degree in Biotechnology at National University of Ireland, Galway in 1996.  He did his thesis work at European Molecular Biology Laboratory Heidelberg, Germany.  There he worked with Prof. Mathias Gautel characterizing proteins that are involved in muscle contraction.  He received his PhD for this work from NUI, Galway in 2000.  For his postdoctoral work he switched to the field of Neuroscience and worked at Duke University in North Carolina with Prof. Guoping Feng funded by a Ruth K. Broad Biomedical Research Foundation Postdoctoral Fellowship.  At Duke he studied the molecular mechanisms of synapse formation in the nervous system.  He also developed a novel technique to genetically manipulate and monitor neurons in transgenic mice. He is currently a College Lecturer and Principal Investigator in the School of Biochemistry Cell Biology at University College Cork, Ireland.

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Paul Young received his undergraduate degree in Biotechnology at National University of Ireland, Galway in 1996.  He did his thesis work at European Molecular Biology Laboratory Heidelberg, Germany.  There he worked with Prof. Mathias Gautel characterizing proteins that are involved in muscle contraction.  He received his PhD for this work from NUI, Galway in 2000.  For his postdoctoral work he switched to the field of Neuroscience and worked at Duke University in North Carolina with Prof. Guoping Feng funded by a Ruth K. Broad Biomedical Research Foundation Postdoctoral Fellowship.  At Duke he studied the molecular mechanisms of synapse formation in the nervous system.  He also developed a novel technique to genetically manipulate and monitor neurons in transgenic mice. He is currently a College Lecturer and Principal Investigator in the School of Biochemistry Cell Biology at University College Cork, Ireland.

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Research Interests



Research Overview

Our research focuses on the cell and molecular biology of neuronal and cancer cells.  Three ongoing strands of research aim to investigate:

1. The mechanisms underlying neural circuit formation and function through the development of novel techniques to label and manipulate neurons in transgenic mice.

2. The roles of the alpha-actinin family of actin-crosslinking proteins at sysnapses and in cell biological processes relevant to cancer such as cell migration.

3. The physiological functions of the LNX family of proteins in the nervous system and their putative involvement in colorectal and brain cancer.

The methodologies that we employ include: mouse molecular genetics, confocal microscopy, protein:protein interaction technologies, biochemical asssays, immunohistochemistry and mouse behavioural assays.


 Current Research Projects

  • Labeling and manipulating neurons to study synaptic connectivity in the nervous system   

Defects in neuronal morphology and synaptic connectivity have been implicated as causative factors in Alzheimer's disease, epilepsy and mental retardation. To better understand the cellular and molecular mechanisms underlying the establishment and modulation of synaptic connectivity we developed a method termed single-neuron labeling with inducible cre-mediated knockout (SLICK), for genetic manipulation of single fluorescently labeled neurons in vivo (1,2).  SLICK reveals the detailed morphology and synaptic connections of genetically manipulated cells within a predominantly wild-type background, providing unprecedented opportunities to assess cell autonomous functions of genes and to study competitive and dynamic aspects of neural circuit formation and function. 

In collaboaration with Susan Dymecki at Harvard University we recently applied SLICK to demonstrate that tetanus toxin light chain expression in vivo caused a reduction in dendritic spine density in a cell-autonomous manner(3).  This effect is likely to be a consequence of inhibition of activity-dependent dendritic exocytosis and suggests that on-going plasticity-associated exocytosis is required for long-term dendritic spine maintenance in vivo. 

References

(1)  P. Young, L. Qiu, D. Wang, S. Zhao, J. Gross, G. Feng, Single-neuron labeling with inducible Cre-mediated knockout in transgenic mice, Nature neuroscience 11 (2008) 721-728.

(2)  V. Heimer-McGinn, P. Young, Efficient inducible Pan-neuronal cre-mediated recombination in SLICK-H transgenic mice, Genesis 49 (2011) 942-949.

(3)  V. Heimer-McGinn, A.C. Murphy, J.C. Kim, S.M. Dymecki, P.W. Young, Decreased dendritic spine density as a consequence of tetanus toxin light chain expression in single neurons in vivo, Neurosci Lett (2013).
 
 

  • Alpha-Actinin family of actin-crosslinking proteins

Actinins are major F-actin cross-linking proteins found in virtually all cell types.  There are four actinin genes, in addiotn to several splicing variants.  Acinin-4 overexpression occurs in many types of cancer and is associated with poor outcomes. In the brain actinin-1,-2 and -4 are postsynaptic components and interact with key mediators of synaptic plasticity such as NMDA type glutamate receptors (NMDAR) and Ca++/Calmodulin dependent protein kinase II (CaMKII).  Further characterisation of the various actinin isoforms is required understand their roles in cancer and synaptic plasticity. 

We have comprehensively investigated the splicing, actin-binding properties, heterodimerisation and molecular interactions of the actinin-1 and 4. We found that the calcium-insensitive variant of actinin-4 is expressed only in the nervous system and thus cannot be regarded as a smooth muscle isoform, as is the case for the calcium-insensitive variant of actinin-1.  The actin-binding properties of actinin-1 and -4 are similar and are unlikely to explain isoform-specific functions.  Surprisingly we observed that actinin-1/-4 heterodimers, rather than homodimers, are the most abundant form of actinin in many cell lines.  The finding that actinin-1 and -4 can readily form heterodimers composed of monomers that may have different properties and interacting proteins significantly alters the predominant view that actinins function primarily as homodimers. 

References

K.S. Foley, P.W. Young, An analysis of splicing, actin-binding properties, heterodimerization and molecular interactions of the non-muscle alpha-actinins, Biochem J 452 (2013) 477-488.
 

  • LNX proteins

LNX proteins are E3 ubiquitin ligases of largely unknown function.  They are closely related and share an identical domain structure consisting of a catalytic RING type E3 ubiquitin ligase domain and several PDZ protien:protein interaction domains.  This combination of domains in one protein is unique to the LNX family. LNX1 and LNX2 were originally identified as ligands of Numb – a protein involved in the specification of cell fates and regulation of neruonal differentiation during development.  Numerous other LNX-binding proteins have been identified however, the in vivo relevance of any of these interactions, including Numb, remains to be demonstrated.  We have examined the molecular evolution of the LNX gene family1 and determined that the LNX genes had an early metazoan origin with a LNX1/LNX2-like protein with 4 PDZ domains likely giving rise to a LNX3/LNX4-like protein through the loss of PDZ domains1.  We are also attempting to identify physiologically relevant LNX interacting proteins and ultimately ellucidate the in vivo functions of this gene family.

References

M. Flynn, O. Saha, P. Young, Molecular evolution of the LNX gene family, BMC Evol Biol 11 (2011) 235. 

Lenihan JA, Saha O, Mansfield LM, Young PW.  Tight, cell type-specific control of LNX expression in the nervous system, at the level of transcription, translation and protein stability. (2014) Gene 552 (1) 39-50.

Research Grants

 ProjectFunding
Body
Start DateEnd DateAward
Characterisation of the LNX3 protein.Irish Research Council for Science, Engineering & Technology (IRCSET)01-OCT-1231-MAR-16€72,000.00

Publications

Book Chapters

 YearPublication
(2018)'Actinin Family'
Young P.W., Ajaykumar A.P. (2018) 'Actinin Family' In: Choi S (eds). Encyclopedia of Signaling Molecules. Cham: Springer. [DOI] [Details]

Peer Reviewed Journals

 YearPublication
(2017)'Decreased anxiety-related behaviour but apparently unperturbed NUMB function in ligand of NUMB protein-X (LNX) 1/2 double knockout mice'
Lenihan, Joan A.; Saha, Orthis; Heimer-McGinn, Victoria; Cryan, John F.; Feng, Guoping; Young, Paul W. (2017) 'Decreased anxiety-related behaviour but apparently unperturbed NUMB function in ligand of NUMB protein-X (LNX) 1/2 double knockout mice'. Molecular Neurobiology, 54 (10):8090-8109 [DOI] [CORA Link] [Details]
(2017)'Proteomic analysis reveals novel ligands and substrates for LNX1 E3 ubiquitin ligase'
Lenihan JA;Saha O;Young PW; (2017) 'Proteomic analysis reveals novel ligands and substrates for LNX1 E3 ubiquitin ligase'. Plos One, 12 (11) [DOI] [Details]
(2016)'Congenital macrothrombocytopenia-linked mutations in the actin-binding domain of alpha-actinin-1 enhance F-actin association'
Murphy, ACH;Lindsay, AJ;McCaffrey, MW;Djinovic-Carugo, K;Young, PW (2016) 'Congenital macrothrombocytopenia-linked mutations in the actin-binding domain of alpha-actinin-1 enhance F-actin association'. Febs Letters, 590 :685-695 [DOI] [Details]
(2016)'Psg22 null mouse embryos develop normally under normoxic and hypoxic conditions of pregnancy'
Williams JM, Bezak T, Das M, Ning Z, Lucking EF, Kelly VP, Harrison P, Young P, O'Connell MJ, Dockery P, O'Halloran KD, Moore T. (2016) 'Psg22 null mouse embryos develop normally under normoxic and hypoxic conditions of pregnancy'. 10.19185/matters.201611000023 [Details]
(2015)'The actinin family of actin cross-linking proteins - a genetic perspective'
Murphy AC, Young PW (2015) 'The actinin family of actin cross-linking proteins - a genetic perspective'. Cell & bioscience, 5 [DOI] [Details]
(2014)'The non-muscle functions of actinins: an update'
Foley KS, Young PW (2014) 'The non-muscle functions of actinins: an update'. The Biochemical Journal, 459 (1):1-13 [DOI] [Details]
(2014)'Tight, cell type-specific control of LNX expression in the nervous system, at the level of transcription, translation and protein stability'
Lenihan, JA;Saha, O;Mansfield, LM;Young, PW (2014) 'Tight, cell type-specific control of LNX expression in the nervous system, at the level of transcription, translation and protein stability'. Gene, 552 :39-50 [DOI] [Details]
(2013)'Decreased dendritic spine density as a consequence of tetanus toxin light chain expression in single neurons in vivo'
Heimer-McGinn, V;Murphy, ACH;Kim, JC;Dymecki, SM;Young, PW (2013) 'Decreased dendritic spine density as a consequence of tetanus toxin light chain expression in single neurons in vivo'. Neuroscience Letters, 555 :36-41 [DOI] [Details]
(2013)'An analysis of splicing, actin-binding properties, heterodimerization and molecular interactions of the non-muscle alpha-actinins'
Foley, KS;Young, PW (2013) 'An analysis of splicing, actin-binding properties, heterodimerization and molecular interactions of the non-muscle alpha-actinins'. The Biochemical Journal, 452 :477-488 [DOI] [Details]
(2011)'Molecular evolution of the LNX gene family'
Flynn, M,Saha, O,Young, P; (2011) 'Molecular evolution of the LNX gene family'. BMC Evolutionary Biology, 11 [DOI] [Details]
(2011)'Efficient inducible Pan-neuronal cre-mediated recombination in SLICK-H transgenic mice'
Heimer-McGinn, V,Young, P (2011) 'Efficient inducible Pan-neuronal cre-mediated recombination in SLICK-H transgenic mice'. Genesis, 49 :942-949 [DOI] [Details]
(2008)'Single-neuron labeling with inducible Cre-mediated knockout in transgenic mice'
Young P, Qiu L, Wang D, Zhao S, Gross J, Feng G; (2008) 'Single-neuron labeling with inducible Cre-mediated knockout in transgenic mice'. Nature Neuroscience, 11 (6):721-728 [DOI] [Details]
(2007)'Regulation of synaptic growth and maturation by a synapse-associated E3 ubiquitin ligase at the neuromuscular junction'
Lu, Z.,Je, H. S.,Young, P.,Gross, J.,Lu, B.,Feng, G.; (2007) 'Regulation of synaptic growth and maturation by a synapse-associated E3 ubiquitin ligase at the neuromuscular junction'. J Cell Biol, 177 (6):1077-89   [Details]
(2005)'LNX1 is a perisynaptic Schwann cell specific E3 ubiquitin ligase that interacts with ErbB2'
Young P., Nie J, Wang X, McGlade CJ, Rich MM, Feng G.; (2005) 'LNX1 is a perisynaptic Schwann cell specific E3 ubiquitin ligase that interacts with ErbB2'. Molecular and Cellular Neuroscience, 30 (2):238-248 [Details]
(2004)'Labeling neurons in vivo for morphological and functional studies'
Young, P.,Feng, G.; (2004) 'Labeling neurons in vivo for morphological and functional studies'. Curr Opin Neurobiol, 14 (5):642-6   [Details]
(2002)'The spectrin repeat: a structural platform for cytoskeletal protein assemblies'
Djinovic-Carugo, K.,Gautel, M.,Ylanne, J.,Young, P.; (2002) 'The spectrin repeat: a structural platform for cytoskeletal protein assemblies'. FEBS Lett, 513 (1):119-23   [Details]
(2001)'Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly'
Young, P.,Ehler, E.,Gautel, M.; (2001) 'Obscurin, a giant sarcomeric Rho guanine nucleotide exchange factor protein involved in sarcomere assembly'. J Cell Biol, 154 (1):123-36   [Details]
(2001)'Crystal Structure of the alpha-Actinin Rod Reveals an Extensive Torsional Twist'
Ylanne, J.,Scheffzek, K.,Young, P.,Saraste, M.; (2001) 'Crystal Structure of the alpha-Actinin Rod Reveals an Extensive Torsional Twist'. Structure (Camb), 9 (7):597-604   [Details]
(2000)'The interaction of titin and alpha-actinin is controlled by a phospholipid-regulated intramolecular pseudoligand mechanism'
Young P and Gautel M.; (2000) 'The interaction of titin and alpha-actinin is controlled by a phospholipid-regulated intramolecular pseudoligand mechanism'. The EMBO Journal, 19 :6331-6340 [Details]
(1999)'Control of sarcomeric assembly: the flow of information on titin'
Gautel, M.,Mues, A.,Young, P.; (1999) 'Control of sarcomeric assembly: the flow of information on titin'. Rev Physiol Biochem Pharmacol, 138 :97-137   [Details]
(1999)'Structure of the alpha-actinin rod: molecular basis for cross-linking of actin filaments'
Djinovic-Carugo, K.,Young, P.,Gautel, M.,Saraste, M.; (1999) 'Structure of the alpha-actinin rod: molecular basis for cross-linking of actin filaments'. Cell, 98 (4):537-46   [Details]
(1998)'Two immunoglobulin-like domains of the Z-disc portion of titin interact in a conformation-dependent way with telethonin'
Mues, A.,van der Ven, P. F.,Young, P.,Furst, D. O.,Gautel, M.; (1998) 'Two immunoglobulin-like domains of the Z-disc portion of titin interact in a conformation-dependent way with telethonin'. FEBS Lett, 428 (1-2):111-4   [Details]
(1998)'Structural basis for activation of the titin kinase domain during myofibrillogenesis'
Mayans, O.,van der Ven, P. F.,Wilm, M.,Mues, A.,Young, P.,Furst, D. O.,Wilmanns, M.,Gautel, M.; (1998) 'Structural basis for activation of the titin kinase domain during myofibrillogenesis'. Nature, 395 (6705):863-9   [Details]
(1998)'Molecular structure of the sarcomeric Z-disk: two types of titin interactions lead to an asymmetrical sorting of alpha-actinin'
Young P, Ferguson C, Banuelos S, Gautel M.; (1998) 'Molecular structure of the sarcomeric Z-disk: two types of titin interactions lead to an asymmetrical sorting of alpha-actinin'. The EMBO Journal, 17 :1614-1624 [Details]
(1997)'Constitutive and variable regions of Z-disk titin/connectin in myofibril formation: a dominant-negative screen'
Peckham, M.,Young, P.,Gautel, M.; (1997) 'Constitutive and variable regions of Z-disk titin/connectin in myofibril formation: a dominant-negative screen'. Cell Struct Funct, 22 (1):95-101   [Details]

Conference Publications

 YearPublication
(2011)EFFICIENT INDUCIBLE NEURON-SPECIFIC CRE-MEDIATED RECOMBINATION IN SLICK-H TRANSGENIC MICE
Young, P,Heimer-Torres, V,Feng, G (2011) IRISH JOURNAL OF MEDICAL SCIENCE EFFICIENT INDUCIBLE NEURON-SPECIFIC CRE-MEDIATED RECOMBINATION IN SLICK-H TRANSGENIC MICE , pp.58-58 [Details]
(2011)ANALYSIS OF LNX1 AND LNX2 EXPRESSION IN THE CENTRAL NERVOUS SYSTEM
Saha, O,Young, P (2011) IRISH JOURNAL OF MEDICAL SCIENCE ANALYSIS OF LNX1 AND LNX2 EXPRESSION IN THE CENTRAL NERVOUS SYSTEM , pp.60-60 [Details]

Professional Activities

Honours and Awards

 YearTitleAwarding Body
2003Scholarship to attend the Neurobiology course at the Marine Biology Laboratory at Woods Hole, Massachusetts. Howard A. Schneiderman Endowed Scholarship and Surdna Foundation
2001Ruth K. Broad Biomedical Research Foundation Postdoctoral Fellowship Ruth K. Broad Biomedical Research Foundation

Professional Associations

 AssociationFunctionFrom / To
Biochemical Society Member Member01-JAN-11 / 31-DEC-15
Neuroscience Ireland Communications Officer Neuroscience Ireland Communications Officer01-JAN-13 / 31-DEC-14
Federation of European Neuroscience Societies Member01-JAN-09 / 01-JAN-15
Neuroscience Ireland Board Member Committee Member01-MAR-09 / 31-DEC-14

Conference Contributions

 YearPublication
(2008)Federation of European Neuroscience Societies (FENS) 6th Forum of European Neuroscience,
Paul Young; (2008) Single-neuron labeling with inducible cre-mediated knockout in transgenic mice. [Oral Presentation], Federation of European Neuroscience Societies (FENS) 6th Forum of European Neuroscience, Geneva, Switzeerland , 01-JUL-08 - 01-JUL-08. [Details]
(2008)Gordon Conference on Neural Ciruits and Disease,
Paul Young; (2008) Single-neuron labeling with inducible cre-mediated knockout in transgenic mice. [Oral Presentation], Gordon Conference on Neural Ciruits and Disease, Oxford UK , 01-AUG-08 - 01-AUG-08. [Details]
(2006)Federation of European Neuroscience Societies (FENS) 5th Forum of European Neuroscience,
Paul Young; (2006) Single-neuron labeling with inducible cre-mediated knockout in transgenic mice. [Poster Presentation], Federation of European Neuroscience Societies (FENS) 5th Forum of European Neuroscience, Vienna, Austria , 08-JUL-06 - 12-JUL-06. [Details]
(2006)Neuroscience Ireland, Inaugural Conference,
Paul Young; (2006) Single-neuron labeling with inducible cre-mediated knockout in transgenic mice. [Poster Presentation], Neuroscience Ireland, Inaugural Conference, University College Cork, Ireland , 21-SEP-06 - 22-SEP-06. [Details]
(2005)Society for Neuroscience (SfN) 35th Annual Meeting,
Paul Young; (2005) LNX1 is a perisynaptic Schwann cell specific E3 ubiquitin ligase that interacts with ErbB2. [Oral Presentation], Society for Neuroscience (SfN) 35th Annual Meeting, Washington, DC, USA , 12-NOV-05 - 16-NOV-05. [Details]
(2005)Society for Neuroscience (SfN) 35th Annual Meeting,
Paul Young; (2005) Single-neuron labeling with inducible cre-mediated knockout in transgenic mice. [Oral Presentation], Society for Neuroscience (SfN) 35th Annual Meeting, Washington, DC, USA , 12-NOV-05 - 16-NOV-05. [Details]
(2002)Society for Neuroscience Annual Meeting,
Paul Young; (2002) Functional characterisation of neuregulin cytoplasmic domain splice variants. [Oral Presentation], Society for Neuroscience Annual Meeting, Orlando, Florida, USA , 01-NOV-02 - 01-NOV-02. [Details]

Committees

 CommitteeFunctionFrom / To
College of SEFS Teaching Learning and Student Experience Committee School Representative2011 /
School Teaching , Learning and Curriculum Committee Chair2014 / 2015
UCC Animal Experimentation Ethics Committee Member2013 /

Employment

 EmployerPositionFrom / To
University College Cork College Lecturer / Principal Investigator01-SEP-05 /
Duke University, Durham, USA Postdoctoral Fellow01-JAN-01 / 01-JAN-05
European Molecular Biology Laboratory, Heidelberg, Germany Postdoctoral Fellow01-JAN-01 / 01-JAN-05

Education

 YearInstitutionQualificationSubject
1996National University of Ireland, Galway, Ireland BScBiotechnology
2000National University of Ireland, Galway, Ireland PhDMol. Biology

Other Activities

 Description

Academic Mentor to UCC and Ireland's first team to participate in iGEM Synthetic Biology competition 2014

Judge at the 2014 iGEM competition (International Genetically Engineered Machine competition in Synthetic Biology)

Teaching Activities

Teaching Interests

I currently teach and/or coordinate the following modules:

  • Introductory Cell Biology and Biomembranes (3rd year Biochemistry; module BC3003).
  • Neuroscience (2nd year Medicine; module FM2101).
  • Neuroscience (2nd year Graduate Entry Medicine; module GM2001).
  • Bone Metabolism and Renal Mechanisms of Homeostasis (2nd year Medicine; module FM2102).
  • Literature review module (3rd year Biochemistry; module BC3012)
  • Biotechnology (4th year Biochemistry: module BC4017)

An outline of these courses and all courses taught by staff in the Department of Biochemistry are available at the UCC Book of Modules.

Recent Postgraduates

 Graduation YearStudent NameInstitutionDegree TypeThesis Title
2013Louise Mansfield UCCMScINVESTIGATION OF LNX PROTEINS WITH REGARD TO STABILITY, TRANSLATIONAL CONTROL AND IN VIVO FUNCTIONS
2013Kate Foley UCCPhDCharacterisation of the non-muscle α-actinins
2013Orthis Saha UCCPhDInvestigation of the function of the LNX family of 
2013Victoria Heimer-McGinn UCCPhDDevelopment and characterization of novel transgenic

Current Postgraduate Students

 StudentDegree Type
Lenihan Joan Anne Doctoral Degree

Modules Taught

 Term (ID))TitleLinkSubject
2019Literature Project BC3012Literature Project
2019Literature Project on Genetics GN3002Literature Project on Genetics
2019Advanced Haematology BM6007Advanced Haematology

Research Information

Internal Collaborators

 NameInstituteCountry
Tommie McCarthy UCCIRELAND
John Cryan UCCIRELAND

External Collaborators

 NameOrganisation / InstituteCountry
Susan Dymecki Dept of Genetics, Harvard UniversityU.S.A.
Manolis Fanto King's College LondonUNITED KINGDOM
Guoping Feng MITU.S.A.

Contact details

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School of Biochemistry and Cell Biology

Scoil na Bithcheimice agus na Cillbhitheolaíochta

University College Cork, Western Road, Cork.

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