Catecholamine Research in the 21st Century. Abstracts and Graphical Abstracts, 10th International Catecholamine Symposium, 2012

308 Pages·2013·22.12 MB·English

by  Lee E. Eiden (Eds.)

Catecholamine Research in
the 21st Century
Abstracts and Graphical Abstracts,
10th International Catecholamine
Symposium, 2012
Catecholamine Research in
the 21st Century
Abstracts and Graphical Abstracts,
10th International Catecholamine
Symposium, 2012
Lee E. Eiden
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Preface
The Tenth International Catecholamine Symposium (XICS) was held at The Asilomar Conference
Grounds in Pacific Grove CA, September 9-13, 2012. It was the first international symposium
focusedon catecholaminesinthe 21st century,providingthe title for theproceedings ofthe sympo-
sium found in this volume. David Goldstein, founding Chief of the Clinical Neurocardiology
Section, NINDS and President of the 8th International Catecholamine Symposium, also held at
Asilomar in 1996, provided the guiding inspiration for the XICS. Daniel O’Connor, Professor of
Medicine and Pharmacology at the Institute for Genomic Medicine, University of California San
Diego, and President of the Catecholamine Society was also President of the 10th International
Catecholamine Symposium. David Sibley, Chief of the Molecular Neuropharmacology Section,
NINDS, Bethesda, MD, Esther Sabban, Professor of Biochemisty and Molecular Biology, New
York Medical College, and the editor of this volume constituted the XICS Executive Organizing
Committee. Many others, most especially the participants who came from Austria, Canada, The
Czech Republic, Denmark, France, Germany, Israel, Italy, Japan, Mexico, Norway, Russian,
Taiwan, the United States and elsewhere, contributed importantly to the success of the XICS. The
editor wishes to thank Dave Goldstein and Dan O’Connor especially for their devotion to the even-
tual completion ofthe Symposium andtheseproceedings.
Some of the broader topics most relevant to the current status of catecholamine research as a trans-
lational field have been covered in greater depth, by thought leaders in catecholamine research who
were in attendance at the XICS, in a companion volume of Advances in Pharmacology. These
include mechanisms of catecholamine biochemistry, cell biology, systems biology, clinical diagno-
sis, drug discovery and target discovery, and gene therapeutic treatment for catecholamine-related
human disease. Contained herein are the comprehensive conference proceedings in the form of
extendedgraphical abstracts, and some condensed abstracts, ofalmost all of the presentations at the
meeting organized into the ten themes under which the symposium was convened. The themes are
introduced as chapters each with a short introduction that attempts to identify the highlights and
’growth areas’ within each. It is hoped that the reader will find these proceedings useful as a hand-
book for the current state of play of catecholamine research, until such time as the Proceedings of
the 11th International Catecholamine Symposium succeeds them.
Lee E. Eiden
Section on Molecular Neuroscience
Laboratory ofCellular andMolecular Regulation
National Institutesof Health
Bethesda, MD, USA
xxi
THEME
A
Catecholamine
Biosynthesis and
Storage
Lee Eiden and David Goldstein
The major features of catecholamine biosynthesis [Tyrosine (TH) (cid:1)> L-Dopa (AADC) (cid:1)> DA
(DBH) (cid:1)> NE (PNMT)(cid:1)> Epi] and storage [cytoplasmic DA, NE, Epi (cid:1)> VMAT1,2(cid:1)> vesicular
DA, NE, Epi] were worked out well before the end of the previous century. This chapter contains
illustrativeexamplesofprogresssince,andthisismanifestinamorecompletemolecularunderstand-
ingofthecellbiologythatallowsTHtocontrolCAbiosynthesis;concreteclinicalstepsfordetection
and gene therapy for catecholamine deficiency diseases; and complete identification of the combina-
tions of catecholamine biosynthetic enzymes and vesicular storage capacity that can be found
throughout the brain and periphery, and distinctly in rodent and primate neuronal systems, from
whicha‘post-classical’viewofcatecholaminechemicalneuroanatomyhasemerged.
While TH retains pride of place as the rate limiting enzyme for catecholamine biosynthesis, new
insights into the conversion of tyrosine to L-Dopa have been gained by fuller exploration of the role
of GTP cyclohydrolase (GTPCH) in supplying the necessary co-factor, tetrahydrobiopterin, for this
enzymaticconversion.GTPCHandTHconvergebiochemicallyontyrosinetoallowitsconversionto
CatecholamineResearchinthe21stCentury. 1
©2014ElsevierInc.Allrightsreserved.
2 THEME A Catecholamine Biosynthesis and Storage
L-Dopa, and thus share in this rate-limiting step for catecholamine production. This provides funda-
mental molecular insights and clinical opportunities. One of the latter is that GTPCH deficiency
occursinhumans,causesdisease,andcanpotentiallybecorrected.
Enzymes in a metabolic pathwayare non-rate-limitingwhentheir increasedoesnot increaseturnover
in the pathway: any enzyme becomes rate-limiting when its decrease or mis-trafficking cause its
abundance to be less than the previous ‘rate-limiting enzyme’ in the pathway. Deficiency of AADC
causes motor impairment that can be corrected by expression of AADC via viral vector-mediated
genedeliverydirectlytothebrain.
Insights into how different types of catecholaminergic neurons develop in the brain have indexed
progress in developmental biology as a field. A surprising new insight is that the brain during devel-
opment may itself be an endocrine organ secreting catecholamines to the rest of the body. The pre-
sumption of developmental neuroscientists that ‘TH-positive’ neurons are dopaminergic or
noradrenergic has been shattered in the last decade: there are DOPAergic and trace aminergic neu-
rons, as well as neuronal dyads that synthesize dopamine only via intercellular collaboration. The
notion that the chemical neuroanatomy of the human nervous system can be fully comprehended by
study of the rodent nervous system has likewise been rendered untenable, and translational neurosci-
ence is far better for it. Finally, exciting new vistas have emerged from the use of genetically-based
lesioning and complementation experiments that show that subdivisions of the major catecholamine
nuclei of the brain, including the locus coeruleus and substantia nigra, have surprising heterogeneity
ofprojectionswithspecificanddistinctfunctions.
Is further progress mainly a matter of effectively executing therapeutic strategies, or do further
questionsremain?Theydo.Itisstillunclearforexample howsupplyofAADCtocellsofthestria-
tum corrects a deficiency that inheres primarily in neurons that project to the striatum. The view
that imaging of VMAT2 with TBZ reflects the molar concentration of the protein in the brain has
given way to an emerging understanding that endogenous catecholamine levels play a role in how
much TBZ binds to VMAT2 in the brains of normals, addicts to methamphetamine or cocaine, and
patients with progressive degenerative disorders. The near-complete success of virus-mediated
correction of brain defects related to catecholamine biosynthesis, and pharmacological correction
of genetic deficiencies in catecholamine storage (see for example Rilstone et al., N. Engl. J. Med.
368, 543, 2013) show that robust clinical gains have resulted from translation of pre-2000 informa-
tion, tools, and advances in allied fields. This in turn predicts that gains in new knowledge reported
in this first, as well as the following chapters of “Catecholamine Research in the 21st Century” will
likelyparlay into further therapeutic gains inthe coming decade.
Genetic Manipulation of Catecholamine Signaling in the Mouse 3
Genetic Manipulation of
Catecholamine Signaling in
the Mouse
Richard Palmiter
UniversityofWashingtonSchoolofMedicineSeattle,Washington,USA
Gene targeting in mouse embryonic stem cells has been used to generate mice that are unable to
synthesize each of the major catecholamines. The developmental and behavioral consequences of
making mice that are unable to synthesize epinephrine, norepinephrine and dopamine will be dis-
cussed. I will illustrate how restoring dopamine signaling to specific brain regions of an otherwise
dopamine-deficient mouse can restore viability and the ability to engage in specific behaviors. I will
also show how we manipulate the activity of dopamine-producing neurons to affect the behavior
ofmice.
AADC Deficiency 3
Genetic Manipulation of
Catecholamine Signaling in
the Mouse
Richard Palmiter
UniversityofWashingtonSchoolofMedicineSeattle,Washington,USA
Gene targeting in mouse embryonic stem cells has been used to generate mice that are unable to
synthesize each of the major catecholamines. The developmental and behavioral consequences of
making mice that are unable to synthesize epinephrine, norepinephrine and dopamine will be dis-
cussed. I will illustrate how restoring dopamine signaling to specific brain regions of an otherwise
dopamine-deficient mouse can restore viability and the ability to engage in specific behaviors. I will
also show how we manipulate the activity of dopamine-producing neurons to affect the behavior
ofmice.
AADC Deficiency: Occurring in
Humans; Modeled in Rodents;
Treated in Patients
Wuh-Liang Hwu1,Ni-Chung Lee1,Yih-DarShieh1,Kai-YuanTzen2,Pin-WenChen1,
Shin-ichiMuramatsu3, Hiroshi Ichinose4 and Yin-Hsiu Chien1
1DepartmentofMedicalGenetics,Pediatrics;2NuclearMedicine,NationalTaiwanUniversityHospital;
3DivisionofNeurology,DepartmentofMedicine,JichiMedicalUniversity,Japan;4DepartmentofLifeScience,
GraduateSchoolofBioscienceandBiotechnology,TokyoInstituteofTechnology,Japan
Aromatic L-amino Acid Decarboxylase (AADC) deficiency (MIM #608643) is an autosomal
recessive inborn error of neurotransmitter metabolism which causes severe motor dysfunction,
oculogyric crisis, autonomic dysfunction, and emotional liability in patients since infancy. AADC
deficiency is more common in Taiwan than in other countries because of a foundermutation
(IVS614A.T). We have established a knock-in (KI) mouse model (DdcIVS6/IVS6) for AADC
deficiency. Some of the homozygous KI mice were born alive, but they exhibited severe failure
to thrive, dyskinesia, and clasping. However, if they could survive their first few weeks of lives,
they then caught up in growth and improved in motor function. Gene therapy at neonatal stage
4 THEME A Catecholamine Biosynthesis and Storage
could eliminate the manifestations of the disease. An attempt to treat patients with AADC
deficiency was initiated before the establishment of the mouse model. AAV2-AADC vectors
were infusued into the bilaterally putamen of four patients 4 to 6 years of age. All of the patients
showed improvements in motor performance: one patient was able to stand 16 months after gene
transfer, and the other three patients gained head controls or achieved supported sitting. Choreic
dyskinesia was observed in all patients, but this resolved after several months. 6-[18F]fluorodopa
positron emission tomography (PET) and cerebrospinal fluid analysis both showed evidences of
the treatment effects.
4 THEME A Catecholamine Biosynthesis and Storage
could eliminate the manifestations of the disease. An attempt to treat patients with AADC
deficiency was initiated before the establishment of the mouse model. AAV2-AADC vectors
were infusued into the bilaterally putamen of four patients 4 to 6 years of age. All of the patients
showed improvements in motor performance: one patient was able to stand 16 months after gene
transfer, and the other three patients gained head controls or achieved supported sitting. Choreic
dyskinesia was observed in all patients, but this resolved after several months. 6-[18F]fluorodopa
positron emission tomography (PET) and cerebrospinal fluid analysis both showed evidences of
the treatment effects.
Tyrosine Hydrolylase and Dopamine
Beta-Hydroxylase: Role of Common
Genetic Variation in Adrenergic
Responses to Stress and in
Hypertension
Daniel O’Connor
UCSD,USA
RATIONALE: Catecholamine biosynthesis is catalyzed by a pathway of reactions in series. We
asked whether the substantial inter-individual variation in catecholaminergic responses was in
part heritable, and referable to genetic variation at loci encoding such enzymes. We also explored
implications of pathway genetic variation for catecholamine secretion, environmental stress
responses, and disease.
METHODS:Wephenotypedcatecholaminergicresponsesintwinpairs(MZandDZ)toestimate
trait heritability (h2), and re-sequenced the tyrosine hydroxylase (TH) and dopamine beta-
hydroxylase (DBH) loci in n580 individuals (i.e., 2n5160 chromosomes) each for systematic
polymorphism discovery. We explored whether such variants predicted catecholamine secretion,
BP responses to environmental stress, or hypertension in the population. Finally, we tested chro-
maffincell-transfectedluciferasereporterplasmidsforconsequencesofpromotervariation.
RESULTS: Both catecholamine secretion and environmental stress (BP response to cold) traits were
substantially heritable as judged by twin pair variance components. Most of the variation at TH and
DBH occurred as bi-allelic SNPs (single nucleotide polymorphisms). Variations within the open
readingframe(ORF),i.e.,non-synonymous(aminoacidreplacement)changes,wereunusual.Bycon-
trast,functional,trait-associatedvariationwaslocalizedtothepromoterregionsofbothTHandDBH.