Human A53T α-Synuclein Causes Reversible Deficits in Mitochondrial Function and Dynamics in Primary Mouse Cortical Neurons
et al. (2013) Human A53T -Synuclein Causes Reversible Deficits in Mitochondrial Function
and Dynamics in Primary Mouse Cortical Neurons. PLoS ONE 8(12): e85815. doi:10.1371/journal.pone.0085815
Human A53T -Synuclein Causes Reversible Deficits in Mitochondrial Function and Dynamics in Primary Mouse Cortical Neurons
Li Li 0
Sashi Nadanaciva 0
Zdenek Berger 0
Wei Shen 0
Katrina Paumier 0
Joel Schwartz 0
Kewa Mou 0
Paula Loos 0
Anthony J. Milici 0
John Dunlop 0
Warren D. Hirst 0
Charleen T Chu, University of Pittsburgh, United States of America
0 1 Neuroscience Research Unit, Pfizer, Inc., Cambridge, Massachusetts, United States of America, 2 Compound Safety Prediction Group, Pfizer, Inc. , Groton, Connecticut , United States of America
Parkinson's disease (PD) is the second most common neurodegenerative disease. A key pathological feature of PD is Lewy bodies, of which the major protein component is -synuclein (-syn). Human genetic studies have shown that mutations (A53T, A30P, E46K) and multiplication of the -syn gene are linked to familial PD. Mice overexpressing the human A53T mutant -syn gene develop severe movement disorders. However, the molecular mechanisms of syn toxicity are not well understood. Recently, mitochondrial dysfunction has been linked with multiple neurodegenerative diseases including Parkinson's disease. Here we investigated whether mitochondrial motility, dynamics and respiratory function are affected in primary neurons from a mouse model expressing the human A53T mutation. We found that mitochondrial motility was selectively inhibited in A53T neurons while transport of other organelles was not affected. In addition, A53T expressing neurons showed impairment in mitochondrial membrane potential and mitochondrial respiratory function. Furthermore, we found that rapamycin, an autophagy inducer, rescued the decreased mitochondrial mobility. Taken together, these data demonstrate that A53T -syn impairs mitochondrial function and dynamics and the deficit of mitochondrial transport is reversible, providing further understanding of the disease pathogenesis and a potential therapeutic strategy for PD.
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Competing interests: All authors are employed by Pfizer Inc. and hold stock in Pfizer Inc. However, this does not alter the authors' adherence to all the
PLOS ONE policies on sharing data and materials.
Parkinsons disease (PD) is the second most common
neurodegenerative disease, affecting 1% of the population
older than 60 and up to 3% of people older than 85 years [1].
This movement disorder is characterized by resting tremor,
rigidity, postural reflex impairment and bradykinesia. Molecular
mechanisms of the disease are still unclear. However, previous
studies have shown that both environmental and genetic
factors play a causal role in PD [2-5].
-synuclein (-syn) is the major protein component of Lewy
bodies, the pathological hallmark of PD [6]. Human genetic
studies have shown that mutations within the -synuclein gene,
A53T, A30P, E46K, and multiplications of this gene are linked
to familial PD [7]. More recently, genome-wide association
(GWAS) studies have also demonstrated that SNCA, which
encodes -syn, is linked to sporadic PD [8]. -syn is an
abundant 140-residue protein, which is primarily found in
neural tissues including the cortex, hippocampus, substantia
nigra, thalamus, cerebellum and spinal cord [9]. It is localized in
the cytosol, nucleus and mitochondria and is enriched
presynaptically. Increased expression of -syn can drive its
aggregation, and A53T -syn has increased propensity to
oligomerize [10] and aggregate into fibrillar forms [11,12]. Mice
expressing A53T -syn develop severe motor deficits leading
to paralysis and death [13]. These animals also develop
agedependent -syn inclusions that recapitulate the pathology
seen in human PD patients. Although -syn plays a critical role
in the pathogenesis of PD the underlying molecular
mechanisms of -syn toxicity are still unclear.
Mitochondrial dysfunction has been linked with multiple
neurodegenerative diseases including PD [14,15]. Recent
reports have shown that -syn exists in mitochondria and can
affect mitochondrial function [16,17]. For example,
overexpression of A53T -syn was shown to inhibit Complex I
activity in the dopaminergic neurons of transgenic mice [18],
depolarize mitochondrial membrane potential and increase
reactive oxygen species in human neuroblastoma cells [19],
and induce mitochondrial autophagy in neurons expressing the
A53T mutation [18,20]. In addition, it was recently shown that
-syn affects mitochondrial motility [21]. In the current study,
we investigated whether the human A53T -syn mutation
expressed in primary cortical neurons from mice affects
mitochondrial transport, membrane potential and respiratory
function and found that all these parameters were impaired in
the presence of the mutant -syn. We also investigated
whether the defective mitochondrial phenotype is reversible
and demonstrated that (...truncated)