10.5061/DRYAD.5MKKWH72Q
Mor, Danielle
0000-0003-3851-5010
Princeton University
Sohrabi, Salman
Princeton University
Kaletsky, Rachel
Princeton University
Keyes, William
Princeton University
Tartici, Alp
Princeton University
Kalia, Vrinda
0000-0003-2244-6663
Columbia University
Miller, Gary
Columbia University
Murphy, Coleen
Princeton University
Data associated with 'Metformin rescues Parkinson’s disease
phenotypes caused by hyperactive mitochondria'
Dryad
dataset
2020
National Cancer Institute
https://ror.org/040gcmg81
NIGMS 5DP1GM119167
Glenn Foundation for Medical Research
https://ror.org/02ebg5q27
GMFR CNV1001899
National Cancer Institute
https://ror.org/040gcmg81
NIEHS U2CES030163
National Cancer Institute
https://ror.org/040gcmg81
NIEHS R01ES023839
National Cancer Institute
https://ror.org/040gcmg81
NIA F32AG062036
2020-09-23T00:00:00Z
2020-09-23T00:00:00Z
en
https://doi.org/10.1101/2020.02.20.958322
https://doi.org/10.1101/2020.02.20.958751
https://doi.org/10.1073/pnas.2009838117
1358613 bytes
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CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
Metabolic dysfunction occurs in many age-related neurodegenerative
diseases, yet its role in disease etiology remains poorly understood. We
recently discovered a potential causal link between the branched-chain
amino acid transferase, BCAT-1, and the neurodegenerative movement
disorder, Parkinson’s disease (PD). RNAi-mediated knockdown of C. elegans
bcat-1 recapitulates PD-like features, including progressive motor
deficits and neurodegeneration with age, yet the underlying mechanisms
have remained unknown. Using transcriptomic, metabolomic, and imaging
approaches, we show here that bcat-1 knockdown increases mitochondrial
respiration and induces oxidative damage in neurons through
mTOR-independent mechanisms. Increased mitochondrial respiration, or
‘mitochondrial hyperactivity,’ is required for bcat-1(RNAi) neurotoxicity.
Moreover, we show that post-disease onset administration of the type 2
diabetes medication, metformin, reduces mitochondrial respiration to
control levels and significantly improves both motor function and neuronal
viability. Together, our findings suggest that mitochondrial hyperactivity
may be an early event in PD pathogenesis, and strategies aimed at reducing
mitochondrial respiration may constitute a surprising new avenue for PD
treatment.
High-resolution metabolomics data was generated using samples collected
per the methods described in the manuscript. Files generated from the
Thermo orbitrap instrument were extracted using the apLCMS and xMSanalyzer
R packages. A feature was retained in the feature table if its intensity
was 1.5 times that of the intensity in the associated bacterial blank
sample and was present in at least 9 of the samples. Null (intensity = 0)
values were replaced with the half the value of the minimum intensity of
that feature.
The feature table has been filtered using bacterial blank samples and null
values of intensity have been imputed.