Loss of MicroRNA-7 Regulation Leads to ?-Synuclein Accumulation and Dopaminergic Neuronal Loss In Vivo.

ABSTRACT: Abnormal alpha-synuclein (?-synuclein) expression and aggregation is a key characteristic of Parkinson's disease (PD). However, the exact mechanism(s) linking ?-synuclein to the other central feature of PD, dopaminergic neuron loss, remains unclear. Therefore, improved cell and in vivo models are needed to investigate the role of ?-synuclein in dopaminergic neuron loss. MicroRNA-7 (miR-7) regulates ?-synuclein expression by binding to the 3' UTR of the Synuclein Alpha Non A4 Component of Amyloid Precursor (SNCA) gene and inhibiting its translation. We show that miR-7 is decreased in the substantia nigra of patients with PD and, therefore, may play an essential role in the regulation of ?-synuclein expression. Furthermore, we have found that lentiviral-mediated expression of miR-7 complementary binding sites to stably induce a loss of miR-7 function results in an increase in ?-synuclein expression in vitro and in vivo. We have also shown that depletion of miR-7 using a miR-decoy produces a loss of nigral dopaminergic neurons accompanied by a reduction of striatal dopamine content. These data suggest that miR-7 has an important role in the regulation of ?-synuclein and dopamine physiology and may provide a new paradigm to study the pathology of PD.

SUBMITTER: McMillan KJ 

PROVIDER: S-EPMC5628933 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature