Cholesterol-
oximes TRO19622 and
TRO40303 target outer mitochondrial membrane
proteins and have beneficial effects in preclinical models of
neurodegenerative diseases leading to their advancement to clinical trials. Dopaminergic neurons degenerate in
Parkinson's disease (PD) and are prone to oxidative stress and
mitochondrial dysfunction. In order to provide insights into the neuroprotective potential of
TRO19622 and
TRO40303 for dopaminergic neurons in vivo, we assessed their effects on gene expression in
laser captured nigrostriatal dopaminergic neurons of wildtype mice and of mice that over-express
alpha-synuclein, a
protein involved in both familial and sporadic forms of PD (Thy1-aSyn mice). Young mice were fed the drugs in food pellets or a control diet from 1 to 4months of age, approximately 10months before the appearance of striatal
dopamine loss in this model. Unbiased weighted gene co-expression network analysis (WGCNA) of transcriptional changes revealed effects of
cholesterol oximes on transcripts related to mitochondria, cytoprotection and
anti-oxidant response in wild-type and transgenic mice, including increased transcription of stress defense (e.g. Prdx1, Prdx2, Glrx2, Hspa9, Pink1, Drp1, Trak1) and
dopamine-related (Th, Ddc, Gch1, Dat, Vmat2, Drd2, Chnr6a) genes. Even at this young age transgenic mice showed alterations in transcripts implicated in mitochondrial function and oxidative stress (e.g. Bcl-2, Bax,
Casp3, Nos2), and both drugs normalized about 20% of these alterations. Young Thy1-aSyn mice exhibit motor deficits that differ from
parkinsonism and are established before the onset of treatment; these deficits were not improved by
cholesterol oximes. However, high doses of
TRO40303 improved olfaction and produced the same effects as
dopamine agonists on a challenging beam test, specifically an increase in footslips, an observation congruent with its effects on transcripts involved in
dopamine synthesis. High doses of
TRO19622 increased
alpha-synuclein aggregates in the substantia nigra; this effect, not seen with
TRO40303 was inconsistent and may represent a protective mechanism as in other
neurodegenerative diseases. Overall, the results suggest that
cholesterol oximes, while not improving early effects of
alpha-synuclein overexpression on motor behavior or pathology, may ameliorate the function and resilience of dopaminergic neurons in vivo and support further studies of neuroprotection in models with dopaminergic cell loss.