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Chronic, low-dose Rotenone Reproduces Lewy Neurites Found in Early Stages of Parkinson's Disease, Reduces Mitochondrial movement and slowly kills differentiated SH-SY5Y Neural cells

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Title Chronic, low-dose Rotenone Reproduces Lewy Neurites Found in
Early Stages of Parkinson's Disease, Reduces Mitochondrial
movement and slowly kills differentiated SH-SY5Y Neural cells
 
Creator Borland, M Kathleen
Trimmer, Patricia A
Rubinstein, Jeremy D
Keeney, Paula M
Mohanakumar, K P
Liu, Lei
Bennett, Jr James P
 
Subject Cell Biology & Physiology
 
Description Background: Parkinson's disease, the most common adult neurodegenerative movement disorder,
demonstrates a brain-wide pathology that begins pre-clinically with alpha-synuclein aggregates ("Lewy
neurites") in processes of gut enteric and vagal motor neurons. Rostral progression into substantia nigra
with death of dopamine neurons produces the motor impairment phenotype that yields a clinical diagnosis.
The vast majority of Parkinson's disease occurs sporadically, and current models of sporadic Parkinson's
disease (sPD) can utilize directly infused or systemic neurotoxins.
Results: We developed a differentiation protocol for human SH-SY5Y neuroblastoma that yielded nondividing
dopaminergic neural cells with long processes that we then exposed to 50 nM rotenone, a
complex I inhibitor used in Parkinson's disease models. After 21 days of rotenone, ~60% of cells died. Their
processes retracted and accumulated ASYN-(+) and UB-(+) aggregates that blocked organelle transport.
Mitochondrial movement velocities were reduced by 8 days of rotenone and continued to decline over
time. No cytoplasmic inclusions resembling Lewy bodies were observed. Gene microarray analyses
showed that the majority of genes were under-expressed. qPCR analyses of 11 mtDNA-encoded and 10
nDNA-encoded mitochondrial electron transport chain RNAs' relative expressions revealed small
increases in mtDNA-encoded genes and lesser regulation of nDNA-encoded ETC genes.
Conclusion: Subacute rotenone treatment of differentiated SH-SY5Y neuroblastoma cells causes process
retraction and partial death over several weeks, slowed mitochondrial movement in processes and
appears to reproduce the Lewy neuritic changes of early Parkinson's disease pathology but does not cause
Lewy body inclusions. The overall pattern of transcriptional regulation is gene under-expression with
minimal regulation of ETC genes in spite of rotenone's being a complex I toxin. This rotenone-SH-SY5Y
model in a differentiated human neural cell mimics changes of early Parkinson's disease and may be useful
for screening therapeutics for neuroprotection in that disease stage.
 
Date 2008
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/153/1/MOLECULAR_NEURODEGENERATION%2C_3(21)%2C2008[1].pdf
Borland, M Kathleen and Trimmer, Patricia A and Rubinstein, Jeremy D and Keeney, Paula M and Mohanakumar, K P and Liu, Lei and Bennett, Jr James P (2008) Chronic, low-dose Rotenone Reproduces Lewy Neurites Found in Early Stages of Parkinson's Disease, Reduces Mitochondrial movement and slowly kills differentiated SH-SY5Y Neural cells. Molecular Neurodegeneration, 3 (21).
 
Relation http://dx.doi.org/10.1186/1750-1326-3-21
http://www.eprints.iicb.res.in/153/