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July 01-02, 2019 | Paris, France
Brain Disorders and Therapeutics
6
th
International Conference on
Journal of Brain and Neurology | Volume: 03
Therapeutic potential of targeting microtubule defects in a mouse model of CDKL5
Deficiency Disorder
Kilstrup-Nielsen C
1
, Barbiero I
1
, Rusconi L, Tramarin T
1
, De Rosa R
1
and
Bianchi M
2
1
University of Insubria, Italy
2
Trinity College Dublin, Ireland
M
utations in the X-linked cyclin-dependent kinase-like
5 (CDKL5) cause CDKL5-deficiency disorder (CDD), a
neurological pathology characterised by severe infantile
seizures, intellectual disability, hypotonia, and impairment
of motor, language and hand function skills. CDKL5-
knockout (KO) mouse models recapitulate most features
of the human disorder including impaired learning and
memory. The absence of CDKL5 causes defective spine
maturation that can at least in part explain the cognitive
impairment of both CDKL5 patients andmousemodels. The
molecular basis for such defect is not clear but may partly
depend on altered microtubule (MT) dynamics. Indeed, we
recently demonstrated that CDKL5 regulates MT dynamics
through CLIP170, a plus end binding protein the mutations
of which are responsible for human intellectual disability.
Our studies suggest that CLIP170 contributes significantly
to the neuronal impairment of CDD and represent an
important druggable target for patients with CDKL5
mutations. The neurosteorid pregnenolone (PREG) can
directly bind and activate CLIP170. Here we present our
data showing that its synthetic derivative pregnenolone-
methyl-ether (PME) rescues CLIP170 functioning in CDKL5
deficient cells and normalizes neuroanatomic, molecular,
and behavioural defects in a mouse model of CDD.
Speaker Biography
Kilstrup-Nielsen C has been working in the University of Insubria,
Department of Biotechnology and Life Sciences Laboratory of
Molecular Neurobiology.
e:
c.kilstrup-nielsen@uninsubria.it