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Neuronal inclusions of α-synuclein contribute to the pathogenesis of Krabbe disease.
[krabbe disease]
Demyelination
is
a
major
contributor
to
the
general
decay
of
neural
functions
in
children
with
Krabbe
disease
.
However
,
recent
reports
have
indicated
a
significant
involvement
of
neurons
and
axons
in
the
neuropathology
of
the
disease
.
In
this
study
,
we
have
investigated
the
nature
of
cellular
inclusions
in
the
Krabbe
brain
.
Brain
samples
from
the
twitcher
mouse
model
for
Krabbe
disease
and
from
patients
affected
with
the
infantile
and
late-onset
forms
of
the
disease
were
examined
for
the
presence
of
neuronal
inclusions
.
Our
experiments
demonstrated
the
presence
of
cytoplasmic
aggregates
of
thioflavin-
S-
reactive
material
in
both
human
and
murine
mutant
brains
.
Most
of
these
inclusions
were
associated
with
neurons
.
A
few
inclusions
were
detected
to
be
associated
with
microglia
and
none
were
associated
with
astrocytes
or
oligodendrocytes
.
Thioflavin-
S-
reactive
inclusions
increased
in
abundance
,
paralleling
the
development
of
neurological
symptoms
,
and
distributed
throughout
the
twitcher
brain
in
areas
of
major
involvement
in
cognition
and
motor
functions
.
Electron
microscopy
confirmed
the
presence
of
aggregates
of
stereotypic
β-sheet
folded
proteinaceous
material
.
Immunochemical
analyses
identified
the
presence
of
aggregated
forms
of
α-synuclein
and
ubiquitin
,
proteins
involved
in
the
formation
of
Lewy
bodies
in
Parkinson
's
disease
and
other
neurodegenerative
conditions
.
In
vitro
assays
demonstrated
that
psychosine
,
the
neurotoxic
sphingolipid
accumulated
in
Krabbe
disease
,
accelerated
the
fibrillization
of
α-synuclein
.
This
study
demonstrates
the
occurrence
of
neuronal
deposits
of
fibrillized
proteins
including
α-synuclein
,
identifying
Krabbe
disease
as
a
new
α-synucleinopathy
.