PMID- 25645689
OWN - NLM
STAT- MEDLINE
DCOM- 20150527
LR  - 20191210
IS  - 1471-4159 (Electronic)
IS  - 0022-3042 (Print)
IS  - 0022-3042 (Linking)
VI  - 133
IP  - 1
DP  - 2015 Apr
TI  - Rotenone decreases intracellular aldehyde dehydrogenase activity: implications 
      for the pathogenesis of Parkinson's disease.
PG  - 14-25
LID - 10.1111/jnc.13042 [doi]
AB  - Repeated systemic administration of the mitochondrial complex I inhibitor 
      rotenone produces a rodent model of Parkinson's disease (PD). Mechanisms of 
      relatively selective rotenone-induced damage to nigrostriatal dopaminergic 
      neurons remain incompletely understood. According to the 'catecholaldehyde 
      hypothesis,' buildup of the autotoxic dopamine metabolite 
      3,4-dihydroxyphenylacetaldehyde (DOPAL) contributes to PD pathogenesis. Vesicular 
      uptake blockade increases DOPAL levels, and DOPAL is detoxified mainly by 
      aldehyde dehydrogenase (ALDH). We tested whether rotenone interferes with 
      vesicular uptake and intracellular ALDH activity. Endogenous and F-labeled 
      catechols were measured in PC12 cells incubated with rotenone (0-1000 nM, 180 
      min), without or with F-dopamine (2 muM) to track vesicular uptake and 
      catecholamine metabolism. Rotenone dose dependently increased DOPAL, F-DOPAL, and 
      3,4-dihydroxyphenylethanol (DOPET) levels while decreasing dopamine and 
      3,4-dihydroxyphenylacetic acid (DOPAC) levels and the ratio of dopamine to the 
      sum of its deaminated metabolites. In test tubes, rotenone did not affect 
      conversion of DOPAL to DOPAC by ALDH when NAD(+) was supplied, whereas the 
      direct-acting ALDH inhibitor benomyl markedly increased DOPAL and decreased DOPAC 
      concentrations in the reaction mixtures. We propose that rotenone builds up 
      intracellular DOPAL by decreasing ALDH activity and attenuating vesicular 
      sequestration of cytoplasmic catecholamines. The results provide a novel 
      mechanism for selective rotenone-induced toxicity in dopaminergic neurons. We 
      report that rotenone, a mitochondrial complex I inhibitor that produces an animal 
      model of Parkinson's disease, increases intracellular levels of the toxic 
      dopamine metabolite 3,4-dihydroxyphenyl-acetaldehyde (DOPAL), via decreased DOPAL 
      metabolism by aldehyde dehydrogenase (ALDH) and decreased vesicular sequestration 
      of cytoplasmic dopamine by the vesicular monoamine transporter (VMAT). The 
      results provide a novel mechanism for rotenone-induced toxicity in dopaminergic 
      neurons.
CI  - (c) 2015 International Society for Neurochemistry.
FAU - Goldstein, David S
AU  - Goldstein DS
AD  - Clinical Neurocardiology Section, CNP/DIR/NINDS/NIH, Bethesda, Maryland, USA.
FAU - Sullivan, Patti
AU  - Sullivan P
FAU - Cooney, Adele
AU  - Cooney A
FAU - Jinsmaa, Yunden
AU  - Jinsmaa Y
FAU - Kopin, Irwin J
AU  - Kopin IJ
FAU - Sharabi, Yehonatan
AU  - Sharabi Y
LA  - eng
GR  - ZIA NS003033-08/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20150225
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (Uncoupling Agents)
RN  - 03L9OT429T (Rotenone)
RN  - 0U46U6E8UK (NAD)
RN  - 102-32-9 (3,4-Dihydroxyphenylacetic Acid)
RN  - EC 1.2.1.3 (Aldehyde Dehydrogenase)
RN  - EC 7.1.1.2 (Electron Transport Complex I)
RN  - VTD58H1Z2X (Dopamine)
SB  - IM
MH  - 3,4-Dihydroxyphenylacetic Acid/metabolism
MH  - Aldehyde Dehydrogenase/*metabolism
MH  - Animals
MH  - Brain Neoplasms/metabolism
MH  - Dopamine/metabolism
MH  - Electron Transport Complex I/drug effects
MH  - Glioblastoma/metabolism
MH  - Glioma/metabolism
MH  - Humans
MH  - NAD/metabolism
MH  - PC12 Cells
MH  - Parkinson Disease, Secondary/*chemically induced/*enzymology
MH  - Rats
MH  - Rotenone/*pharmacology
MH  - Uncoupling Agents/*pharmacology
PMC - PMC4361358
MID - NIHMS665077
OTO - NOTNLM
OT  - 3,4-dihydroxyphenyl-acetaldehyde
OT  - Parkinson's disease
OT  - aldehyde dehydrogenase
OT  - rotenone
OT  - vesicular monoamine transporter
EDAT- 2015/02/04 06:00
MHDA- 2015/05/28 06:00
PMCR- 2016/04/01
CRDT- 2015/02/04 06:00
PHST- 2014/11/20 00:00 [received]
PHST- 2015/01/08 00:00 [revised]
PHST- 2015/01/12 00:00 [accepted]
PHST- 2015/02/04 06:00 [entrez]
PHST- 2015/02/04 06:00 [pubmed]
PHST- 2015/05/28 06:00 [medline]
PHST- 2016/04/01 00:00 [pmc-release]
AID - 10.1111/jnc.13042 [doi]
PST - ppublish
SO  - J Neurochem. 2015 Apr;133(1):14-25. doi: 10.1111/jnc.13042. Epub 2015 Feb 25.