ABSTRACT: BackgroundParkinson'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.
ResultsWe developed a differentiation protocol for human SH-SY5Y neuroblastoma that yielded non-dividing 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.
ConclusionSubacute 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.
Molecular Neurodegeneration 04/2012; 3(1):1-12. · 4.28 Impact Factor