Tau Promotes Neurodegeneration
via DRP1 Mislocalization In Vivo
Brian DuBoff,1Ju ¨rgen Go ¨tz,2and Mel B. Feany1,*
1Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
2Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St. Lucia Campus, QLD 4072, Australia
Mitochondrial abnormalities have been documented
in Alzheimer’s disease and related neurodegenera-
tive disorders, but the causal relationship between
mitochondrial changes and neurodegeneration, and
the specific mechanisms promoting mitochondrial
dysfunction, are unclear. Here, we find that expres-
sion of human tau results in elongation of mitochon-
dria in both Drosophila and mouse neurons. Elonga-
tion is accompanied by mitochondrial dysfunction
and cell cycle-mediated cell death, which can be
rescued in vivo by genetically restoring the proper
balance of mitochondrial fission and fusion. We
have previously demonstrated that stabilization of
actin by tau is critical for neurotoxicity of the protein.
Here, we demonstrate a conserved role for actin and
myosin in regulating mitochondrial fission and show
that excess actin stabilization inhibits association of
the fission protein DRP1 with mitochondria, leading
to mitochondrial elongation and subsequent neuro-
toxicity. Our results thus identify actin-mediated
disruption of mitochondrial dynamics as a direct
mechanism of tau toxicity in neurons in vivo.
Alzheimer’s disease (AD) is the most common neurodegenera-
tive disorder, affecting approximately 10% of people over the
age of 70 (Plassman et al., 2007). AD is characterized histopath-
ologically by deposition of Abeta peptides in extracellular
amyloid plaques and by aggregation of hyperphosphorylated
species of the microtubule-associated protein tau into neurofi-
brillary aggregates in the cytoplasm of neurons. Experimental
evidence supports the amyloid cascade hypothesis in which
Abeta peptides act upstream of tau to mediate neurodegenera-
tion in AD (Hardy and Selkoe, 2002; Ittner and Gotz, 2011).
Importantly, dominant, highly penetrant mutations in the tau
(MAPT) gene cause the familial neurodegenerative disease fron-
totemporal dementia with parkinsonism linked to chromosome
17 (FTDP-17), demonstrating anunequivocalrolefor tauinmedi-
ating neurodegeneration in patients (Hutton et al., 1998; Poorkaj
et al., 1998; Spillantini et al., 1998). AD and related disorders
characterized by abnormal deposition of tau are collectively
Despite the substantial evidence linking tau to neurodegener-
ation, the mechanisms downstream of tau that promote
dysfunction and death of neurons are still incompletely under-
stood. A potential role for abnormalities of mitochondrial struc-
ture and function in tauopathies has been attractive for a number
of reasons. First, mitochondria are critical regulators of a variety
of important cellular processes, including ATP production and
metabolism of reactive oxygen species. Second, abnormalities
in mitochondrial function have been strongly linked to aging,
the most important risk factor for AD (Bratic and Trifunovic,
2010). In addition, mitochondrial morphological defects have
been observed in patients with AD (Hirai et al., 2001). A number
of reports have suggested dysfunction of mitochondria in tauop-
athy patients and disease models, based on reduced levels of
mitochondrial metabolic proteins, including pyruvate dehydro-
genase (Perry et al., 1980), ATP synthase (David et al., 2005),
and Complex I (Rhein et al., 2009). Although these data taken
together argue convincingly for mitochondrial abnormalities in
AD and related tauopathies, the precise nature of the funda-
mental defects and the causal role those defects play in disease
pathogenesis has been unclear.
In the current study, we demonstrate increased length of
mitochondria in animal models of tauopathy. Mitochondrial
morphology is regulated by reciprocal membrane fission and
fusion, termed mitochondrial dynamics. In mammalian cells,
outer mitochondrial membrane fusion is induced by mitofusin-
1 and mitofusin-2 (MFN1 and MFN2) and inner membrane fusion
by OPA1 (Chen et al., 2003; Cipolat et al., 2004). Mitochondrial
fission is dependent on the dynamin-related GTPase DRP1,
which is primarily cytoplasmic with a smaller fraction localizing
to the outer mitochondrial membrane (Smirnova et al., 2001).
Translocation of DRP1 from cytoplasm to mitochondria appears
to play a critical role in the regulation of fission (Frank et al.,
2001). Rare inherited neurological disorders reveal the impor-
tance of normal mitochondrial dynamics in postmitotic neurons.
Charcot-Marie-Tooth disease type 2A (CMT2A), a progressive
sensory and motor axonopathy, is caused by mutations in
MFN2 (Zu ¨chner et al., 2004). Similarly, mutations in OPA1
underlie the autosomal dominant optic atrophy syndrome,
a degeneration that targets retinal ganglion cells (Alexander
et al., 2000; Delettre et al., 2000). Additionally, a severe neurode-
velopmental syndrome has been reported in a patient with
a dominant negative mutation in DRP1 (Waterham et al., 2007).
However, the contribution of abnormal mitochondrial dynamics
618 Neuron 75, 618–632, August 23, 2012 ª2012 Elsevier Inc.
to the pathogenesis of common neurodegenerative diseases,
like AD, has been less clear.
To take a genetic approach to the mechanisms underlying
neurodegeneration in AD and related tauopathies, we have
developed a Drosophila model that recapitulates a number of
salient features of the human disorders. Expression of wild-
type and mutant versions of human tau in flies results in aberrant
phosphorylation and aggregation of tau, progressive neurode-
generation, and early death (Wittmann et al., 2001; Jackson
et al., 2002; Nishimura et al., 2004; Khurana et al., 2010). We
have subsequently defined a number of mechanisms that are
critical for neurodegeneration in our tauopathy model. These
mechanisms are implicated in human AD and related tauopa-
thies, as well. Neurotoxicity in our system requires phosphoryla-
tion of tau as an early event (Steinhilb et al., 2007a, 2007b;
Iijima-Ando et al., 2010). Tau then directly binds to and stabilizes
actin (Fulga et al., 2007). However, the mechanism by which
actin stabilization promotes downstream mediators of neuro-
toxicity has been unclear. The molecular machinery that drives
mitochondrial dynamics is well conserved in Drosophila (Ver-
streken et al., 2005; Hwa et al., 2002). We now identify actin-
mediated DRP1 mislocalization as a critical effector of tau
neurotoxicity in postmitotic neurons and further show that
DRP1 localization to mitochondria requires the actin-based
motor protein myosin II.
Tau Expression Promotes Mitochondrial Elongation
Our Drosophila model of tauopathy is based on expression of
either wild-type or FTDP-17 linked mutant forms of tau in
neurons using the UAS/GAL4 bipartite expression system
(Brand and Perrimon, 1993) and a panneuronal driver (elav-
GAL4). In these studies, we predominantly express human tau
carrying the R406W mutation, which, unless otherwise noted,
we will refer to as ‘‘tau’’ for simplicity. We have previously found
that the enhanced toxicity observed with expression of R406W
mutant tau facilitates examination of neurodegeneration in the
aging brain, with good conservation of mechanisms underlying
neurotoxicity between mutant and wild-type forms of human
tau (Khurana et al., 2006, 2010; Fulga et al., 2007; Dias-
Santagata et al., 2007; Loewen and Feany, 2010). To examine
mitochondrial morphology in our model, we coexpressed tau
with mitochondrially localized GFP (mitoGFP) in neurons of
the adult brain. Visualizing the neuronally expressed and mito-
chondrially directed GFP reveals normal round to tubular mito-
chondria in control neurons (Figure 1A, control, arrowheads). In
contrast, mitochondria in the neurons of brains from flies ex-
pressing tau are markedly elongated (Figure 1A, tau, arrow-
heads). Quantification shows that in tau-expressing neurons
mitochondrial length is, on average, greater than twice that of
control (Figure 1A, graph). Consistent with a causative role for
altered mitochondrial dynamics in mediating tau neurotoxicity,
mitochondrial elongation precedes cell death and increases
with age (Figures S1A and S1E available online). Mitochondrial
elongation also correlates with in vivo toxicity of different forms
of tau. Expression of tauR406Winduces greater mitochondrial
elongation compared to expression of wild-type human tau
(tauWT) expressed at the same levels, consistent with enhanced
toxicity of tauR406Wcompared to tauWT(Wittmann et al., 2001;
Khurana et al., 2006). Even greater elongation is triggered by
expression of a more toxic, pseudohyperphosphorylated form
of tau (tauE14, Figure S1B) (Dias-Santagata et al., 2007; Loewen
and Feany, 2010), suggesting that mitochondrial elongation is
downstream of tau phosphorylation.
Because a significant body of evidence links abnormalities of
axonal transport to tauopathy pathogenesis (Ebneth et al., 1998;
Dixit et al., 2008; Kopeikina et al., 2011; Ittner et al., 2009), we
wondered if elongation of mitochondria in tau transgenic
animals might be a secondary effect related to a defect in trans-
port of mitochondria out of the cell body, rather than a primary
abnormality. We thus evaluated mitochondrial length following
inhibition of axonal transport of mitochondria. The miro and
milton proteins are essential for association of mitochondria
with the motor protein kinesin, which facilitates their microtu-
bule-based transport (Glater et al., 2006). Consistent with
a role for miro in mitochondrial trafficking, transgenic RNAi-
mediated reduction of miro increases the mitochondrial content
of the neuronal cell bodies. However, mitochondria in miro
knockdown neurons are not elongated (Figure 1A, miro RNAi,
arrowheads). Similarly, in clones homozygous for milton92,
a null mutation (Glater et al., 2006), mitochondria are increased
in neuronal soma but are unchanged in length (Figure S1A).
Further, reduction of miro function does not alter mitochondrial
morphology in the presence of transgenic tau but is instead
associated with increased numbers of both normal and elon-
gated mitochondria in the neuronal cell bodies, as well as
enhancement of tau neurotoxicity (Figures S1D and S1E).
Thus, elongation of mitochondria in tau transgenic animals
does not appear to be a secondary effect of axonal transport
We next determined if tau expression can alter mitochondrial
morphology in vertebrate neurons. We used a murine model of
tauopathy, rTg4510, in which human tau carrying the FTDP-17
linked P301L mutation is expressed using the CaMKIIa
promoter (Ramsden et al., 2005; Santacruz et al., 2005). To
visualize mitochondria in histologic sections from these trans-
genic mice, we performed immunofluorescent staining for ATP
synthase. We observe round to modestly tubular mitochondria
in hippocampal pyramidal neurons of control mice (Figure 1B,
control, arrowheads). In contrast, mitochondria specifically in
hippocampal pyramidal neurons, a vulnerable cell population
in these tau transgenic mice, have elongated morphology (Fig-
ure 1B, tau, arrowheads). Quantitative analysis reveals a signifi-
cant increase in mean mitochondrial length in hippocampal
neurons from tau transgenic mice (Figure 1B, graph). We
observe similar mitochondrial elongation in a second murine
model of tauopathy, K3, in which the FTDP-17-associated
mutant form of tau carrying the K369I mutation is expressed
under the control of the mThy1.2 promoter (Ittner et al., 2008).
Mitochondrial elongationis prominent in frontal cortical
neurons, which express high levels of tau in these animals (Fig-
ure S1F). Three-dimensional reconstruction of confocal fluores-
cence Z-stacks captured from Drosophila and murine neurons
affords a more detailed view of the elongated morphology and
Tau Induces DRP1 Mislocalization
Neuron 75, 618–632, August 23, 2012 ª2012 Elsevier Inc. 619
interconnected organization of mitochondria induced by human
tau expression (Movies S1, S2, S3, and S4).
Reversing Mitochondrial Elongation Rescues
Neurotoxicity In Vivo
To determine if toxicity of tau to postmitotic neurons is influ-
enced by the mitochondrial elongation we observe in animal
models, we manipulated the mitochondrial dynamics machinery
genetically. We focused on DRP1 and MARF (the fly homolog of
mammalian MFN) and increased and decreased expression of
each protein. To increase net mitochondrial fission levels, we
overexpressed DRP1 and decreased levels of MARF using
transgenic RNAi. These modifications significantly reduce mito-
chondrial length in tau transgenic flies (Figure 2A). Importantly,
normalization of mitochondrial length is accompanied by signif-
Figure 1. Tau Expression Promotes Mito-
chondrial Elongation in Neurons In Vivo
(A) Immunofluorescent staining for GFP in neurons
of flies expressing mitochondrially targeted GFP
(mitoGFP) reveals normal round to modestly
tubular mitochondria in control flies of the geno-
type elav-GAL4/+; UAS-mitoGFP/+
arrowheads). Mitochondria in tau transgenic flies
are elongated (tau, arrowheads). Reduction of
miro (miro RNAi) increases the number of mito-
chondria in neuronal soma but does not alter
mitochondrial morphology (arrowheads). Nuclei
are stained with DAPI. Scale bar is 2 mm. Quanti-
fication of mean mitochondrial length for control
and tau transgenic neurons is displayed in the
graph. Asterisk indicates p < 0.01, unpaired t test,
n = 6. Control (ctrl) is elav-GAL4/+.
(B) Immunofluorescent staining for ATP synthase
in CA1 hippocampal neurons of control mice
demonstrates normal modestly tubular mito-
chondria (control, arrowheads). Mitochondria in
hippocampal neurons from human tau P301L
transgenic mice are elongated (tau, arrowheads).
Nuclei are stained with DAPI. Scale bar is 5 mm.
Quantification of mean mitochondrial length for
control and tau transgenic neurons is displayed in
the graph. Asterisk indicates p < 0.01, unpaired t
test, n = 3.
See also Figure S1.
icant rescue of neurotoxicity, as moni-
tored with TUNEL staining to identify
dying neurons (Figure 2B). Reduction of
MARF or increase of DRP1 does not
produce significant mitochondrial short-
ening or neuronal toxicity in the absence
of human tau expression using the
genetic modifiers indicated.
We then performed genetic manipula-
tions that altered dynamics in the recip-
rocal fashion, toward increased fusion,
by overexpressing MARF or reducing
DRP1 through transgenic RNAi. When
we increase fusion, we observe a further
increase in mitochondrial length in tau
transgenic flies. Enhanced mitochondrial elongation is accom-
panied bysignificantly increased neurodegeneration (Figure 2B).
Tovalidate the effectsof DRP1 andMARF depletion byRNAi, we
used a loss of function DRP1 mutant (DRP1T26; Verstreken et al.,
2005) and a chromosomal deficiency for the MARF locus (MARF
def.; Parks et al., 2004), both of which modify mitochondrial
length and neurotoxicity in tau transgenic flies (Figures S2B
and S2C). We also find that a loss-of-function mutation in
OPA1-like (OPA1-likeS3475, Spradling et al., 1999), the fly
homolog of the mammalian OPA1 fusion gene, normalizes mito-
chondrial length and suppresses toxicity in our Drosophila tau-
opathy model (Figures S2B and S2C). No significant effect on
mitochondrial morphology or neurodegeneration is observed
when DRP1 is reduced in the absence of transgenic human tau
expression, consistent with the relatively modest reduction of
Tau Induces DRP1 Mislocalization
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