Download Slides: Abstract SAT 465 - Loh

SAT 465
A Novel Mutation of the Human
Carboxypeptidase E Gene Results in Loss of
Neuroprotective Function
Y. Peng Loh , Lin Cong, Yong Cheng, Niamh X. Cawley and Saravana R.K. Murthy
Section on Cellular Neurobiology, Eunice Kennedy Shriver National Institute of Child
Health and Human Development, NIH, Bethesda, MD 20892
Introduction
1. Carboxypeptidase E (CPE) is a prohormone processing enzyme and recently it is also
known as Neurotrophic factor α-1
2. Intracellularly, CPE is an exopeptidase involved in cleaving
C-terminal basic amino acid residues from endoproteolytically cleaved prohormone
intermediates. It also acts as a sorting receptor at the trans Golgi network for
directing prohormones to the regulated secretory pathway.
3. CPE acts extracellularly as a neurotrophic factor involved in neuroprotection,
anti-depression and stem cell differentiation.
Homozygous CPE null mutation
CLINICAL FEATURES:
Obesity: At the time of examination, she had a
weight of 130.2 kg and height of 1.59 m with body
mass index (BMI) 51.5 kg/m2.
Type 2 Diabetes: she had glucose level 383 mg/dL,
HbA1c 114 mmol/mol.
Hypogonadotrophic hypogonadism: primary
amenorrhea (serum oestradiol 78 pmol/L [postmenopausal range <100 pmol/L], 21.2 pg/mL; LH
2.7 IU/L, FSH 2.0 IU/L). Serum hormone analysis
excluded other causes of amenorrhoea including
polycystic ovary syndrome and
hyperprolactinaemia (testosterone
1.2 nmol/L (normal <2.7), 0.35 ng/mL (normal
<0.78); normal androstenedione, 17hydroxyprogesterone,
dehydroepiandrosterone sulphate (DHEAS),
prolactin).
Intellectual disability: despite adequate schooling
she was unable to read or write words.
Ref: Alsters et al 2015 PlosOne 10(6):e0131417
KO
WT
Absence of CPE/NF-α1 leads to obesity, diabetes, infertility, neurodegeneration,
learning and memory deficits and depression.
WT
KO
CPE
6weeks
Nissl
6weeks
Weaning stress
at 3 weeks.
Nissl
3weeks
Note
hippocampal
CA3
region
degeneration
A human carboxypeptidase E /NF-α1 gene mutation in an
Alzheimer’s disease patient leads to memory loss , dementia and
depression in mice
Cheng Y, Cawley NX, Yanik T, Murthy SR, Liu C, Kasikci F, Abebe D, Loh YP.
Transl Psychiatry. 2016 Dec 6;6(12):e973. doi: 10.1038/tp.2016.237.
{
Histopathology of CPE-QQ and WT mouse hippocampus (50weeks old).
(a) Confocal images showing fewer dendrites indicating neurodegeneration in
CPE-QQ mice
(b) Confocal images showing hyper phosphorylation of tau in DG of hippocampus
QQ mice.
(c, d) Western blot analysis more tau phosphorylation in hippocampus of CPE-QQ
than WT mice. t-test, n=6, *P<0.05.
T to C CPE mutation was found in human
Mutation found in 12.5 % of the AGI_ASP population of patients made up of 40
African-Americans and Caucasians (dbSNPrs cluster id: rs34516004).
(PLoS One. 2017 Jan 23;12(1):e0170169)
TC CPE mutation has no enzymatic activity
Over expression of TC CPE on neuroprotection
Decreased expression and secretion of TC-CPE
and loss of neuroprotective activity
TC CPE “hijacks” WT CPE
Decreased secretion of WT-CPE when coexpressed with CPE-QQ
TC-CPE increases ER stress
Conclusions
1) T980C mutation of the CPE gene causes ER stress, poor secretion of
the mutant protein and diminished neuroprotective activity against
oxidative stress in N2A cells, unlike WT-CPE which is neuroprotective.
2) Humans homozygous for this mutation is expected to result in
obesity, diabetes and neurodegeneration. Humans heterozygous for
this mutation is expected to result in the reduction of WT protein by a
dominant recessive mechanism leading to neurodegeneration .
3) CPE is a potential therapeutic target for treating neurodegenerative
disease.
4) Rosiglitazone, an anti-diabetic drug which up-regulates CPE
expression is a potential drug for treating dementia.