G-protein coupled receptor 88 knockdown in the associative striatum reduces psychiatric symptoms in a translational male rat model of Parkinson disease.

Background: In addition to motor disability, another characteristic feature of Parkinson disease is the early appearance of psychiatric symptoms, including apathy, depression, anxiety and cognitive deficits; treatments for these symptoms are limited by the development of adverse effects such as impulse-control disorders. In this context, we investigated the orphan G protein-coupled receptor 88 (GPR88) as a novel therapeutic target.

Methods: We used lentiviral-mediated expression of specifically designed microRNA to knock down Gpr88 in a translational male rat model of early Parkinson disease obtained by dopamine loss in the dorsolateral striatum as a result of 6-hydroxydopamine lesions.

Altered age-linked regulation of plasma DYRK1A in elderly cognitive complainers (INSIGHT-preAD study) with high brain amyloid load.

Introduction: An effective therapy has not yet been developed for Alzheimer's disease (AD), in part because pathological changes occur years before clinical symptoms manifest. We recently showed that decreased plasma DYRK1A identifies individuals with mild cognitive impairment (MCI) or AD, and that aged mice have higher DYRK1A levels.

Methods: We assessed DYRK1A in plasma in young/aged controls and in elderly cognitive complainers with low (L) and high (H) brain amyloid load.

Knock-Down of GPR88 in the Dorsal Striatum Alters the Response of Medium Spiny Neurons to the Loss of Dopamine Input and L-3-4-Dyhydroxyphenylalanine.

The effects of L-3-4-dyhydroxyphenylalanine (L-DOPA) treatment for replacing the dopamine (DA) loss in Parkinson's disease (PD) progressively wear off and are hindered by the development of dyskinesia, prompting the search for new treatments. The orphan G protein-coupled receptor 88 (Gpr88) represents a potential new target, as it is highly and almost exclusively expressed in the projecting gamma-Aminobutyric Acid-ergic (GABAergic) medium spiny neurons of the striatum, is implicated in motor activity, and is downregulated by 6-hydroxydopamine (6-OHDA) lesions, an effect that is reversed by L-DOPA. Thus, to evaluate Gpr88 as a potential target for the management of PD and L-DOPA-induced dyskinesia (LID), we inactivated Gpr88 by lentiviral-mediated knock-down with a specifically designed microRNA (miR) (KD-Gpr88) in a 6-OHDA rat model of hemiparkinsonism.