ASCB 2013 PressBook - page 12

T H E A M E R I C A N S O C I E T Y F O R C E L L B I O L O G Y
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13
News from
The American Society
for Cell Biology
53rd Annual Meeting
New Orleans, LA
December 14–18, 2013
Following the link from Gaucher disease
to Parkinson’s disease
EMBARGOED
FOR RELEASE
10:00 am, U.S. Central Time
Tuesday, December 17, 2013
Contact
Mia Horowitz
Dept. Cell Research and
Immunology
Tel Aviv University
Ramat Aviv, 69978, Israel
+972-3-6409285
Author Presents
Tuesday, December 17, 2013
12:00 PM–1:30 PM
Aging and Aging-Associated
Degeneration
Presentation 2238
Poster B1221
Exhibit Halls B–D
The connection between UPR,
Gaucher Disease, and Parkinson’s
disease
G. Maor
1
, D. Segal
2
, H. Steller
3
,
M. Horowitz
1
1
Cell Research and Immunology,
Tel Aviv University, Ramat Aviv,
Israel
2
Biotechnology and Molecular
Microbiology, Tel Aviv University,
Ramat Aviv, Israel
3
Laboratory of Apoptosis and
Cancer Research, Rockefeller
University, New York, New York
A genetic lipid-processing disease
and a late-onset neurodegenerative
disease may be connected through
a defective lysosomal enzyme
I
t seems an unlikely connection, and
yet there is a significant link between
Gaucher disease (GD), a purely genetic
disease affecting lipid storage, and Parkinson’s
disease, a largely untreatable progressive
degenerative movement disorder of the
central nervous system that is often with-
out a clear genetic cause. Those born with
two recessive GD mutations, which cause a
dangerous build-up of lipids, have a higher
risk of developing Parkinson’s disease than
those with normal GD genes. More surpris-
ing is the higher risk for Parkinson’s disease
among carriers of GD mutation who have no
overt GD symptoms, but still produce some
level of the defective enzyme
called
.
Since the normal job
of
is to
chop up certain lipids, it
might be expected that GD
carriers would accumulate
these lipids, but this is not
the case. Instead, the prob-
lem seems to be caused by
accumulation of the defec-
tive enzyme itself, leading
to the activation of cellular
machines that dispose of
defective proteins. When
these machines get too busy,
they can trigger a cascade
that leads to cell death.
In Parkinson’s, it is the
death of specific cells in the
brain, dubbed dopaminergic
cells, that leads to develop-
ment of the disease. Mia
Horowitz and Gali Maor of
Tel Aviv University and
colleagues hypothesized
that this cell death cascade
is the link to Parkinson’s
disease. They set out to make
a laboratory model of carriers of GD
mutations to test their idea using
Drosophila
melanogaster,
the easily re-engineered fruit
fly. They mutated the GD enzyme, glucocer-
ebrosidase, in a subset of neurons in fruit
flies. With defective
,
these flies began losing their dopamine-
generating neurons, a classic symptom of
Parkinson’s disease. Also, the
Drosophila
had reduced climbing ability, the fly equiv-
alent of Parkinsonian hypokinesis, the
characteristic movement “freeze-up.”
This is the first animal model in which
carriers of GDmutations have demonstrated
Parkinson’s-like symptoms, says Horowitz.
The fly model thus lends support to the idea
that GD and Parkinson’s disease are related
through the pathways triggered by accumu-
lation of defective proteins, a cascade that
leads to dopaminergic cell death.
Flies expressing mutant human glucocerebrosidase develop Parkin-
sonian signs.
(TOP) Flies expressing different human mutant glucocer-
ebrosidase variants have less TH containing cells in their brain at 22 days
(the circles specify dopaminergic cells, expressing TH) and (BOTTOM) have
locomotion deficit as tested by their climbing ability at different days. The
stars underscore the significance of the difference between flies express-
ing normal human glucocerebrosidase and flies expressing mutant human
glucocerebrosidase (N370S or L444P).
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