Journal of Clinical Investigation,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 26, 2024
Lysosomes
are
implicated
in
a
wide
spectrum
of
human
diseases
including
monogenic
lysosomal
storage
disorders
(LSDs),
age-associated
neurodegeneration
and
cancer.
Profiling
content
using
tag-based
immunoprecipitation
(LysoTagIP)
cell
animal
models
has
substantially
moved
the
field
forward,
but
studying
dysfunction
patients
remains
challenging.
Here,
we
report
development
'tagless
LysoIP'
method,
designed
to
enable
rapid
enrichment
lysosomes,
via
immunoprecipitation,
endogenous
integral
membrane
protein
TMEM192,
directly
from
clinical
samples
lines
(e.g.,
induced
pluripotent
stem
derived
neurons).
Isolated
lysosomes
were
intact
suitable
for
subsequent
multimodal
omics
analyses.
To
validate
our
approach,
applied
tagless
LysoIP
enrich
peripheral
blood
mononuclear
cells
fresh
healthy
donors
with
CLN3
disease,
an
autosomal
recessive
neurodegenerative
LSD.
Metabolic
profiling
isolated
revealed
massive
accumulation
glycerophosphodiesters
(GPDs)
patients'
lysosomes.
Interestingly,
patient
milder
phenotype
genotype
displayed
lower
GPDs,
consistent
their
potential
role
as
disease
biomarkers.
Altogether,
provides
framework
study
native
samples,
identify
biomarkers,
discover
human-relevant
mechanisms.
Molecular Cell,
Journal Year:
2024,
Volume and Issue:
84(7), P. 1354 - 1364.e9
Published: March 5, 2024
Batten
disease,
the
most
prevalent
form
of
neurodegeneration
in
children,
is
caused
by
mutations
CLN3
gene,
which
encodes
a
lysosomal
transmembrane
protein.
loss
leads
to
significant
accumulation
glycerophosphodiesters
(GPDs),
end
products
glycerophospholipid
catabolism
lysosome.
Despite
GPD
storage
being
robustly
observed
upon
loss,
role
GPDs
neuropathology
remains
unclear.
Here,
we
demonstrate
that
act
as
potent
inhibitors
lysosome
using
human
cell
lines
and
mouse
models.
Mechanistically,
bind
competitively
inhibit
phospholipases
PLA2G15
PLBD2,
establish
possess
phospholipase
B
activity.
effectively
rate-limiting
lysophospholipase
activity
these
phospholipases.
Consistently,
lysosomes
CLN3-deficient
cells
tissues
accumulate
toxic
lysophospholipids.
Our
work
establishes
material
disease
directly
disrupts
lipid
homeostasis,
suggesting
clearance
potential
therapeutic
approach
this
fatal
disease.
Annual Review of Biochemistry,
Journal Year:
2024,
Volume and Issue:
93(1), P. 447 - 469
Published: April 11, 2024
Lysosomes
catabolize
and
recycle
lipids
other
biological
molecules
to
maintain
cellular
homeostasis
in
diverse
nutrient
environments.
Lysosomal
lipid
catabolism
relies
on
the
stimulatory
activity
of
bis(monoacylglycero)phosphate
(BMP),
an
enigmatic
whose
levels
are
altered
across
myriad
lysosome-associated
diseases.
Here,
we
review
discovery
BMP
over
half
a
century
ago
its
structural
properties
that
facilitate
activation
hydrolases
recruitment
their
coactivators.
We
further
discuss
current,
yet
incomplete,
understanding
anabolism.
To
conclude,
role
diseases
potential
for
modulating
by
pharmacologically
activating
inhibiting
synthase
therapeutically
target
lysosomal
storage
disorders,
drug-induced
phospholipidosis,
Alzheimer's
disease,
Parkinson's
frontotemporal
dementia,
cancer,
viral
infection.
ACS Nano,
Journal Year:
2024,
Volume and Issue:
18(11), P. 8051 - 8061
Published: March 6, 2024
The
intracellular
clustering
of
anisotropic
nanoparticles
is
crucial
to
the
improvement
localized
surface
plasmon
resonance
(LSPR)
for
phototherapy
applications.
Herein,
we
programmed
process
spiky
(SNPs)
by
encapsulating
them
into
an
anionic
liposome
via
a
frame-guided
self-assembly
approach.
liposome-encapsulated
SNPs
(lipo-SNPs)
exhibited
distinct
and
enhanced
lysosome-triggered
aggregation
behavior
while
maintaining
excellent
monodispersity,
even
in
acidic
or
protein-rich
environments.
We
explored
enhancement
photothermal
therapy
performance
as
proof
concept.
conversion
efficiency
lipo-SNPs
clusters
significantly
increased
15
times
compared
that
single
lipo-SNPs.
Upon
accumulation
lysosomes
with
2.4-fold
increase
clustering,
resulted
cell-killing
45%
from
12%
at
24
μg/mL.
These
findings
indicated
encapsulation
provides
promising
approach
programing
nanoparticle
target
site,
which
facilitates
advances
development
smart
nanomedicine
programmable
LSPR.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 2, 2025
Abstract
CLN5
disease,
a
form
of
juvenile
dementia
within
the
neuronal
ceroid
lipofuscinosis
(NCL),
is
associated
with
mutations
in
gene
encoding
lysosomal
bis(monoacylglycero)phosphate
(BMP)
synthase,
essential
for
BMP
production
and
function.
Limited
knowledge
cellular
mechanisms
unclear
drug
targets
hinder
translating
this
to
children’s
treatment,
which
remains
symptomatic.
We
developed
characterized
new
cln5
knock-out
zebrafish
model
that
replicates
key
features
molecular
signatures
human
disease.
Loss
Cln5
function
vivo
altered
axonal
growth
retinal
ON-bipolar
cells
revealing
disease
features.
Additionally,
multi-omic
analyzes
at
different
developmental
stages,
revealed
an
impaired
glucose
metabolism
as
original
finding
NCL.
This
work
demonstrates
profound
metabolic
impact
dysfunction,
offering
promising
avenue
toward
targeted
therapies
dementia.
