Mutant Huntingtin: Nuclear translocation and
cytotoxicity mediated by GAPDH
Byoung-Il Bae*, Makoto R. Hara*†, Matthew B. Cascio*, Cheryl L. Wellington‡, Michael R. Hayden§,
Christopher A. Ross*†¶?, Hyo Chol Ha*,**, Xiao-Jiang Li††, Solomon H. Snyder*†¶‡‡§§, and Akira Sawa*†¶§§
Departments of *Neuroscience,¶Psychiatry,?Neurology, and‡‡Pharmacology, and†Program in Cellular Molecular Medicine, Johns Hopkins University
School of Medicine, Baltimore, MD 21205; Departments of‡Pathology and Laboratory Medicine and§Molecular Medicine and Therapeutics, University
of British Columbia, Vancouver, BC, Canada V5Z 4H4; **Department of Biochemistry and Molecular Biology, Georgetown University Medical Center,
Washington, DC 20057; and††Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322
Contributed by Solomon H. Snyder, December 30, 2005
The pathophysiology of Huntington’s disease reflects actions of
mutant Huntingtin (Htt) (mHtt) protein with polyglutamine re-
peats, whose N-terminal fragment translocates to the nucleus to
associated cytotoxicity of mHtt reflect a ternary complex of mHtt
with GAPDH and Siah1, a ubiquitin-E3-ligase. Overexpression of
GAPDH or Siah1 enhances nuclear translocation of mHtt and
cytotoxicity, whereas GAPDH mutants that cannot bind Siah1
prevent translocation. Depletion of GAPDH or Siah1 by RNA inter-
ference diminishes nuclear translocation of mHtt.
Huntington’s disease ? Siah ? polyglutamine
in the N-terminal region of Htt (1). In cell culture models,
overexpression of mutant Htt (mHtt) with the expanded polyQ,
especially the N-terminal mHtt fragments, elicits cytotoxicity
that requires nuclear translocation of the N-terminal fragment
(2, 3). In a variety of HD animal models, nuclear accumulation
of mHtt is also critical for HD pathophysiology (4–7). Accord-
ingly, understanding the mechanism of the nuclear translocation
may shed light on the neurotoxicity and potential therapy
Recently, we described a cell-death cascade involving
stimulate inducible or neuronal forms of nitric oxide (NO)
synthase with NO S-nitrosylating GAPDH, conferring upon it
the ability to bind to Siah1, a ubiquitin-E3-ligase. Siah1, which
possesses a nuclear localization signal (NLS), elicits the trans-
location of GAPDH to the nucleus. In the nucleus, GAPDH
stabilizes the rapidly turning over Siah, enabling it to degrade its
nuclear protein targets, leading to cell death. We wondered
whether the GAPDH?Siah1 cascade participates in the nuclear
translocation of mHtt. In the present study, we demonstrate that
GAPDH, together with Siah, facilitates nuclear translocation of
mHtt and resultant neurotoxicity.
untington’s disease (HD) is a genetically dominant disorder
caused by expansion of a polyglutamine (polyQ) sequence
Htt and other proteins with polyQ repeats have been reported
to bind to GAPDH (9, 10). To determine whether such binding
is relevant to the nuclear targeting of mHtt and its cytotoxicity,
we have explored this interaction in detail. First, we directly
demonstrate in vitro protein binding of GAPDH to an N-
terminal fragment of Htt (His-Htt-N171-23Q) (Fig. 1A), which
was confirmed in a yeast two-hybrid assay (Htt-N427, data not
shown). We then examined potential interactions of wild-type
by monitoring coimmunoprecipitation (Fig. 1B). Siah1, but not
GAPDH, levels are elevated in whole-cell lysates with mHtt
after cytotoxic insult (8). GAPDH precipitates to the same
extent with wtHtt and mHtt, whereas Siah1 coprecipitates much
more with mHtt than with wtHtt. Under basal conditions, Siah1
self-degrades through its ubiquitin-E3-ligase activity mediated
by its RING finger domain (11). To prevent confounding effects
of Siah self degradation, we transfected Siah1 lacking the RING
finger domain (Siah1?RING), which provides total lysate levels
Nonetheless, substantially greater Siah1?RING coprecipitates
with mHtt than with wtHtt. Accordingly, Siah1 does bind more
avidly to GAPDH?Htt complexes containing expanded polyQ.
To determine whether GAPDH and Siah1 are responsible for
the nuclear translocation of mHtt, we conducted subcellular
fractionation of N2a cells, a mouse neuroblastoma cell line, after
transfection with GAPDH or with a mutant GAPDH in which
lysine-225 is replaced with alanine (GAPDH-K225A) (Fig. 2A).
We previously showed that K225 is critical for the binding of
GAPDH to Siah1, so that GAPDH-K225A fails to translocate to
the nucleus (8). In the presence of mHtt, we observe substantial
levels of GAPDH, but not GAPDH-K225A, in the nucleus (data
not shown). Nuclear mHtt levels are also augmented after
transfection of GAPDH. Transfection of GAPDH-K225A leads
to substantially less nuclear mHtt. Thus, GAPDH and its
interaction with Siah1 appear critical for nuclear translocation of
mHtt, and both mHtt and GAPDH accumulate within the
To assess the domains of Siah1 that are critical for nuclear
translocation of mHtt, we cotransfected N2a cells with wild-type
Siah1, Siah1 lacking its NLS (Siah1?NLS), or Siah?RING (Fig.
2B). Transfection with Siah1 or Siah1?NLS reduces nuclear as
well as total cell levels of mHtt, presumably because the ubiq-
uitin-E3-ligase activity of Siah1 degrades mHtt. The ratio of
nuclear to total mHtt in cells is tripled after Siah1 overexpres-
sion. Siah’s NLS mediates the nuclear translocation of mHtt,
because Siah1?NLS fails to augment the ratio of nuclear to total
mHtt. In contrast, overexpression of Siah1?RING leads to
increases of both indicators. Thus, both GAPDH and Siah
mediate nuclear translocation of mHtt.
Many studies have established an important role for nuclear
translocation of mHtt in eliciting cytotoxicity (2, 3). Accord-
ingly, we monitored cell death in N2a cells using various
GAPDH and Siah1 constructs to determine whether GAPDH
and Siah1 modulate mHtt-induced cytotoxicity (Fig. 3A).
Overexpression of GAPDH or Htt-Associated Protein-1
(HAP-1) does not cause notable cell death. By contrast,
overexpression of mHtt is cytotoxic, and combined transfec-
Conflict of interest statement: No conflicts declared.
Abbreviations: HD, Huntington’s disease; polyQ, polyglutamine; Htt, Huntingtin; mHtt,
mutant Htt; wtHtt, wild-type Htt; RNAi, RNA interference; Siah1?RING, Siah1 lacking the
RING finger domain; GAPDH-K225A, mutant GAPDH in which lysine-225 is replaced with
§§To whom correspondence may be addressed. E-mail: email@example.com or asawa1@
© 2006 by The National Academy of Sciences of the USA
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tion with GAPDH augments this toxicity, whereas combined
transfection with HAP-1 does not. Enhanced toxicity with
GAPDH is observed in mHtt with two different lengths of the
N-terminal fragment. Overexpression of expanded polyQ itself
also elicits cytotoxicity that is substantially increased by
GAPDH transfection, whereas overexpression of a nonpatho-
genic glutamine tract (23 glutamines) is not cytotoxic, even in
the presence of overexpressed GAPDH. We also monitored
the influence of Siah1 on cytotoxicity. In the absence of mHtt,
neither Siah1?NLS nor Siah1?RING is cytotoxic, consistent
with our previous studies (8). In cells overexpressing mHtt,
transfection with Siah1?RING markedly increases cell death,
whereas overexpressing Siah1?NLS does not. We did not
examine Siah1 by itself, because the intrinsic cytotoxicity of
Siah1 would confound evaluations of mHtt toxicity.
Because GAPDH is a major glycolytic enzyme, it is conceiv-
able that the protein interaction of GAPDH and mHtt may
influence cytotoxicity via changes in cellular energy status.
Accordingly, we examined the influence of mHtt on GAPDH
catalytic activity in N2a cell extracts and on intracellular levels
of ATP (Fig. 3B). Overexpression of mHtt does not affect
GAPDH catalytic activity. In confirmation of our earlier study
(8), mutation of cysteine-150 to serine abolishes catalytic activity
of the transfected mutant GAPDH. GAPDH transfection dou-
bles cellular ATP levels with a similar augmentation observed in
cells overexpressing mHtt. GAPDH-C150S does not influence
Most of the experiments described above involved overex-
pression of proteins. To assess the importance of endogenous
GAPDH and Siah1 for nuclear translocation of mHtt, we
depleted proteins by RNA interference (RNAi). In N2a cells, as
we reported in other cells, treatment with RNAi almost totally
depletes mRNA levels for both GAPDH and Siah1 (data not
shown). As described (8, 12), we added pyruvate to maintain
cellular energy status. In control cells, about half of the inclu-
sions detected by immunofluorescent staining are intranuclear.
Depletion of GAPDH or Siah1 reduces nuclear inclusion levels
by 50–60% (Fig. 4 A and B). By contrast, there is a substantial
increase of perinuclear inclusions in the GAPDH and Siah1-
depleted cells with no major change in cytoplasmic inclusions.
We recently reported that nuclear translocation of Htt in human
lymphoblasts involves specific perinuclear sites (13). These find-
trafficking between the perinuclear and nuclear compartments
rather than between the cytoplasm and the perinuclear region.
In the present study, we provide a mechanism for nuclear
translocation of mHtt that involves a ternary complex of mHtt,
GAPDH, and Siah1.
A role of GAPDH?Siah1 in mediating the nuclear transloca-
tion of mHtt reflects a function for GAPDH?Siah1. In our
and Siah1 mediates cell death induced by a variety of stressors
(8, 14). GAPDH stabilizes Siah1 in the nucleus and augments
Siah1-associated toxicity. By contrast, in the present study,
Siah1?RING, which by itself is nontoxic, augments mHtt-
induced cytotoxicity. Thus, GAPDH and Siah1 influence the
sorting of mHtt to the nucleus, independent of the GAPDH?
Siah1 death cascade (8). There exist two distinct forms of human
Siah, Siah1 and Siah2 (15). Most of the experiments in the
present study have used Siah1. In preliminary studies, deletion
of Siah2 by RNAi also reduces the nuclear translocation of mHtt
(B.-I.B. and S.H.S., unpublished observations).
Our findings implicate the GAPDH?mHtt interaction in HD
pathology. In early studies describing the binding of Htt to
GAPDH, it was speculated that altered glycolytic activity of
GAPDH might play a role in the pathophysiology (9, 16). We
observed that augmentation of mHtt cytotoxicity by GAPDH is
unrelated to decreases in GAPDH glycolytic activity or ATP
content of cells. Similarly, Beal and coworkers (17) as well as
Shapira and coworkers (18) have failed to find altered GAPDH
activity in brains of patients with HD, although there is a report
of a slight change of GAPDH in the caudate of HD brain (19).
Presumably, in neurons with mHtt, oxidized GAPDH translo-
cates to the nucleus together with Siah, facilitating nuclear
translocation of mHtt. Chuang and coworkers (20) recently
detected nuclear accumulation of GAPDH in a transgenic
mouse model of HD, fitting with our findings. Nuclear GAPDH
in HD fibroblasts migrates aberrantly in glycerol gradient sed-
imentations, suggesting that GAPDH in patient tissues is incor-
porated into a protein complex of a large molecular weight,
N-terminal 171 amino acids and 23 polyQ (His-N171-23Q) were purified from Escherichia coli. In vitro binding assay was performed on glutathione beads. (B)
as shown by coimmunoprecipitation (co-IP). The Htt protein complex was immunoprecipitated by myc antibody and immunoblotted with Htt (EM48), GAPDH,
and HA antibodies. (Left) Siah1, a rapidly turning-over protein, is stabilized (input) and recruited to the Htt-GAPDH complex (IP) to a greater extent with
N171-148Q than with N171-23Q. (Center) Siah1?RING is resistant to self degradation, leading to comparable protein levels in N171-23Q and N171-148Q-
transfected cells (input). More Siah1?RING is recruited to the Htt-GAPDH complex by N171-148Q than by N171-23Q (IP). PolyQ expansion does not affect the
interaction of GAPDH and Htt. (Right) Densitometric analysis of coIP shows that mHtt is better than wtHtt in recruiting Siah1 and Siah1?RING. Data represent
the mean and SEM of two independent experiments (t test,*, P ? 0.01).
Htt, GAPDH, and Siah1 form a ternary complex. (A) GAPDH binds to Htt in vitro. GST-tagged GAPDH (GST-GAPDH) and His-tagged Htt containing
www.pnas.org?cgi?doi?10.1073?pnas.0511316103Bae et al.
probably with mHtt (21). In the present study, such a complex is
implied by the smearing of GAPDH immunoreactivity together
of that of mHtt near the gel top in Western blots (data not
Li and coworkers (22) have described an alternate means
whereby mHtt might enter the nucleus. They showed that
N-terminal fragments of Htt bind to the nuclear pore protein
translocated promoter region (Tpr) that participates in nuclear
export. A lesser binding of mHtt to this protein is associated with
greater nuclear accumulation. Reducing the expression of Tpr
increases nuclear accumulation of mHtt. Conceivably, dimin-
ished interactions of mHtt with Tpr function in concert with the
GAPDH-Siah1 system in mediating nuclear translocation.
Exact mechanisms whereby nuclear mHtt elicits cytotoxicity
are still unclear. There are several candidate proteins that
interact with mHtt and mediate cytotoxicity, including cAMP
response element-binding protein, Sp1, and p53 (23). In both
cellular and animal models of HD, p53 is up-regulated, and
blockade of p53 diminishes mitochondria-associated cellular
dysfunctions and cytotoxicity as well as behavioral abnormalities
of HD mice (24). Abnormalities of p53 in HD are not evident in
spinocerebellar ataxia type-1 (SCA1) (25). Interestingly,
ataxin-1, atrophin-1, and the androgen receptor, whose polyQ
expansions are responsible for SCA1, dentatorubral pallidoluy-
sian atrophy, and spinobulbar muscular atrophy, bind to
GAPDH in a manner similar to Htt (9, 10). In preliminary
studies, we showed that cytotoxicity induced by mutant atro-
phin-1 is also increased by overexpression of GAPDH (A.S. and
S.H.S., unpublished data). These results suggest that GAPDH
may have a common role in modulating the pathophysiology of
Materials and Methods
Reagents and Constructs. Unless otherwise noted, reagents were
obtained from Sigma. All Htt, GAPDH, and Siah plasmids were
previously described (8, 24). Short oligomers of RNAi to
GAPDH, Siah1, Siah2, and control were synthesized (Dharma-
con Research, Lafayette, CO), following the sequences previ-
ously described. Antibodies against GAPDH (Biogenesis,
Bournemouth, U.K.), Htt EM48 (Chemicon), hemagglutinin
to 15-fold in N2a cells transfected with FLAG-tagged mHtt and GAPDH. The binding of GAPDH to Siah1 is critical for nuclear targeting of mHtt, because
GAPDH-K225A, which fails in binding to Siah1 and translocating to the nucleus, leads to significantly less nuclear mHtt than GAPDH (t test,*, P ? 0.01;**, P ?
0.001). (B) Overexpressed Siah1 augments nuclear targeting of mHtt in N2a cells transfected with mHtt and Siah1. Overexpressed Siah1 and Siah1?NLS degrade
both total and nuclear mHtt through the ubiquitin-E3-ligase activity of Siah1, as Siah1 lacking ubiquitin-E3-ligase activity (Siah1?RING) only increases nuclear
targeting of mHtt 2- to 3-fold without degrading mHtt. It is noticeable that the ratio of nuclear to total mHtt is tripled by overexpression of Siah1, but not
Siah1?NLS (ANOVA,*, P ? 0.01). The bracket indicates SDS-insoluble mHtt aggregates. Data represent the mean and SEM of three independent experiments.
Overexpressed GAPDH and Siah1 enhance nuclear targeting of mHtt. (A) Overexpressed GAPDH augments nuclear targeting of mHtt (N171-82Q) 10-
Bae et al. PNAS ?
February 28, 2006 ?
vol. 103 ?
no. 9 ?
(HA) (Sigma), FLAG (Sigma), Myc (Roche Applied Science,
Indianapolis), Histone H2B (Upstate Biotechnology, Lake
Placid, NY), and ?-tubulin (Upstate Biotechnology) were pur-
In Vitro Binding. His-tagged Htt N171-23Q and GST-tagged
GAPDH proteins were prepared and used for in vitro binding by
following the detailed protocol previously described (8, 24, 26).
Coimmunoprecipitation. Homogenates of HEK293T cells trans-
fected with 2 ?g of myc-tagged Htt N171-23Q?148Q and 6 ?g of
HA-tagged Siah1 or Siah1?RING (60-mm dishes) for 48–60 h
were prepared in ice-cold 500 ?l of RIPA lysis buffer (150 mM
NaCl?1% Nonidet P-40?0.5% sodium deoxycholate?0.1%
SDS?50 mM Tris?Cl, pH 8.0) containing protease inhibitors and
1 mM EDTA. Htt was immunoprecipitated with 2 ?g of myc
antibody, and the presence of GAPDH and Siah1 or
Siah1?RING in the Htt protein complex was examined through
immunoblotting with anti-GAPDH and HA antibodies. Effi-
ciency of immunoprecipitation of Htt was confirmed with the
EM48 antibody. Siah binding to the Htt and GAPDH complex
was analyzed by densitometry.
Nuclear Fractionation. By using N2a cells transfected with 2 ?g of
dishes) for 48–60 h, the nuclei were obtained from the cell lysates
in buffer B (10 mM Tris?Cl, pH 7.4?0.4% Nonidet P-40?0.25 M
sucrose?10 mM MgCl2?10 mM KCl?1 mM DTT, and protease
inhibitors without EDTA) by centrifugation over a 2-M sucrose
cushion (10 mM Tris?Cl, pH 7.4?1.7 M sucrose?10 mM MgCl2?10
mM KCl?1 mM DTT) at 100,000 ? g for 1 h (14). Immunoblotting
and HA antibodies. Histone H2B and ?-tubulin levels were used as
loading controls. Levels of nuclear mHtt and the ratio of nuclear to
total mHtt were analyzed by densitometry.
GAPDH Enzymatic Activity and Intracellular ATP Levels. GAPDH
glycolytic activity and intracellular ATP in N2a cells were
measured as described (8, 27).
transfected with Htt and GAPDH, Htt-Associated Protein-1 (HAP-1), Siah1?RING, or Siah1?NLS for 72 h. GAPDH, but not HAP-1, augments cytotoxicity of mHtt
N171-82Q, mHtt N427-148Q (mHtt containing N-terminal 427 amino acids and 148 polyQ), and 82 polyQ (82Q), suggesting the specificity of GAPDH. GAPDH is
not toxic in itself or with 23 polyQ (23Q). Siah1?RING, but not Siah1?NLS, significantly augments mHtt toxicity. (B) Enhanced mHtt cytotoxicity by GAPDH is
independent of GAPDH glycolytic activity or intracellular ATP levels. Overexpressed GAPDH augments glycolytic activity and the ATP level, which is not affected
by mHtt N171-82Q expression. GAPDH-C150S harbors a mutation at the catalytic center, debilitating enzymatic activity of GAPDH (t test,*, P ? 0.01).
Overexpressed GAPDH and Siah1?RING increase mHtt cytotoxicity. (A) Overexpressed GAPDH and Siah1?RING augment mHtt cytotoxicity in N2a cells
was transfected into N2a cells pretreated with siRNA to GAPDH or Siah1. Medium was supplemented with 1 mM pyruvate to avoid toxicity of GAPDH siRNA.
Intranuclear inclusions are frequently observed with control RNAi but not with GAPDH siRNA or Siah1 siRNA. When nuclear targeting of mHtt is significantly
randomly chosen fields 36 h after transfection performed in triplicate (t test,*, P ? 0.01).
Depletion of GAPDH and Siah1 blocks nuclear targeting of mHtt. mHtt containing N-terminal 67 amino acids and 104Q fused to GFP (N67-104Q-GFP)
www.pnas.org?cgi?doi?10.1073?pnas.0511316103Bae et al.
Cell Culture and Transfection. N2a and HEK293T cells were Download full-text
cultured in DMEM containing 10% FBS and nonessential amino
acids. Pyruvate-supplemented culture media were used to com-
pensate potential energy deficits by RNAi to GAPDH, accord-
ing to the established protocol (8). Lipofectamine 2000 (Invitro-
gen) was used for transfection, following the manufacturer’s
protocol. The ratio of plasmids to lipofectamine 2000 was 1:4
(wt?wt), and that of RNAi to lipofectamine 2000 was 1:50,000
(wt?wt) to get the highest transfection efficiency with minimal
toxicity. For cotransfection of Htt and GAPDH or Siah1 into a
60-mm dish culture, 2 ?g of Htt and 6 ?g of GAPDH or Siah1
plasmids was used to ensure coexpression. For cotransfection of
Htt and RNAi into a 60-mm-dish culture, 0.4 ng of RNAi, 2 ?g
of plasmid, and 20 ?g of lipofectamine 2000 were used.
Cell Death Assay. Cytotoxicity was monitored by using a lactate
dehydrogenase (LDH) assay kit (Sigma). LDH in the media and
within N2a cells was measured. In parallel, we monitored the
transfection efficiency by GFP signal. The LDH ratio of media
supernatant to total cell extract was standardized by the trans-
fection efficiency to obtain the percentage of dead cells.
Confocal Microscopic Quantification of Nuclear Targeting of mHtt.
Thirty-six hours after the first transfection of RNAi to GAPDH,
Siah1, or Siah2 into N2a cells, RNAi and N67-104Q-GFP were
introduced together, and the cells were analyzed 24?36 h later.
In this way, residual GAPDH and Siah1 were depleted by the
time mHtt was expressed. Visible mHtt inclusions in the cyto-
plasmic, perinuclear, or nuclear domains scored under confocal
microscopy (PerkinElmer UltraVIEW) were used to assess
nuclear targeting of mHtt. Inclusions bound to the nuclear
membranes without nuclear entry were considered ‘‘perinu-
clear.’’ The nuclei were stained with Hoechst 33258 (Invitrogen).
Subcellular localization was determined by overlaying GFP, the
Hoechst signal, and bright-field images. In the same condition,
immunoblotting was also performed to confirm microscopic
quantifications (data not shown).
Densitometry and Statistical Analysis. Quantitative densitometric
analysis of immunoblotting was performed by using the EAGLE-
SIGHT program (Stratagene). Two-tailed P values were calcu-
lated by Student’s t test and ANOVA by using MINITAB 13
(Minitab, State College, PA).
We thank Y. Lema and B. Ziegler for organizing the manuscript. We
thank Xiaojiang Luo and Lisa J. Hanle for technical assistance and
Dr. H. Y. Zoghbi (Baylor College of Medicine, Houston) for providing
GAPDH and the Ataxin-1 constructs . This work was supported by U.S.
Public Health Service Grants MH-069853 (to A.S.) and DA-00266 (to
S.H.S.), Research Scientist Award DA-00074 (to S.H.S.), and by grants
from the National Alliance for Research on Schizophrenia and Depres-
sion and the Stanley and S-R Foundations (to A.S.).
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