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A structural and functional analysis of Nna1 in Purkinje cell degeneration (pcd) mice.
[canavan disease]
The
axotomy-inducible
enzyme
Nna
1
defines
a
subfamily
of
M
14
metallocarboxypeptidases
,
and
its
mutation
underlies
the
Purkinje
cell
degeneration
(
pcd
)
mouse
.
However
,
the
relationship
among
its
catalytic
activity
,
substrate
specificities
,
and
the
critical
processes
of
neurodegeneration
/
axon
regeneration
is
incompletely
understood
.
Here
we
used
a
transgenic
rescue
strategy
targeting
expression
of
modified
forms
of
Nna
1
to
Purkinje
cells
in
pcd
mice
to
determine
structure-activity
relationships
for
neuronal
survival
and
in
parallel
characterized
the
enzymatic
properties
of
purified
recombinant
Nna
1
.
The
Nna
1
subfamily
uniquely
shares
conserved
substrate-determining
residues
with
aspartoacylase
that
,
when
mutated
,
cause
Canavan
disease
.
Homologous
mutations
(
D
1007
E
and
R
1078
E
)
inactivate
Nna
1
in
vivo
,
as
does
mutation
of
its
catalytic
glutamate
(
E
1094
A
)
,
which
implies
that
metabolism
of
acidic
substrates
is
essential
for
neuronal
survival
.
Consistent
with
reports
that
Nna
1
is
a
tubulin
glutamylase
,
recombinant
Nna
1
-
but
not
the
catalytic
mutants-removes
glutamate
from
tubulin
.
Recombinant
Nna
1
metabolizes
synthetic
substrates
with
2
or
more
C-
terminal
glutamate
(
but
not
aspartate
)
residues
(
V
(
max
)
for
3
glutamates
is
∼
7
-
fold
higher
than
2
glutamates
although
K
(
M
)
is
similar
)
.
Catalysis
is
not
ATP
/
GTP
dependent
,
and
mutating
the
ATP
/
GTP
binding
site
of
Nna
1
has
no
effect
in
vivo
.
Nna
1
is
a
monomeric
enzyme
essential
for
neuronal
survival
through
hydrolysis
of
polyglutamate-containing
substrates
.
Diseases
Validation
Diseases presenting
"catalytic mutants-removes glutamate"
symptom
canavan disease
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