New therapeutic targets for Parkinson’s disease and comorbid psychiatric disorders

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by a progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc). L-DOPA combined with peripheral inhibitors of L-aromatic amino acid decarboxylase (LAAD) is the standard of care in the pharmacological management of PD. L-DOPA is highly effective in the first years of treatment, and then its use is complicated by the occurrence of motor and non-motor fluctuations and involuntary movements (L-DOPA-induced dyskinesias or LIDs). Other drugs include MAO-B and COMT inhibitors, dopamine receptor agonists, and anticholinergic agents. None of these drugs slow the progression of PD, and the discovery of disease modifying agents is urgently needed. In addition, the pharmacological control of non-motor signs of PD (e.g., depression, cognitive dysfunction, and neuropathic pain) is so far an unmet need. My PhD project includes preclinical and clinical studies aimed at discovering novel targets in the treatment of PD and comorbid depression. Two targets have been identified within the PhD project: the mGlu3 metabotropic glutamate receptors, and the PERK pathway of the unfolded protein response. Using mice, we have demonstrated that the genetic lack of mGlu3 receptors amplifies nigro-striatal degeneration induced by the parkinsonian neurotoxin, MPTP, and reduces the expression of genes encoding anti-inflammatory proteins and neurotrophic factors in the neostriatum (the target region of nigral dopaminergic neurons). In addition, we have found that genetic variants of GRM3 (encoding the mGlu3 receptors) are associated with PD and, more specifically, with motor and non-motor sings of the disorder. In another study we have found that PERK and ATF4 (a gene target of the PERK pathway) are associated with PD. These findings may lay the groundwork for the development of selective mGlu3 receptor agonists or positive allosteric modulators, and/or inhibitors of the PERK pathway as potential disease modifying agents in PD. During my PhD project, I have also performed clinical studies on safinamide, a last generation MAO- B inhibitor, which cater the potential to slow the progression of PD and restrain the occurrence of LIDs in fluctuating patients. In addition, I performed one of the first studies of the antidepressant 2 vortioxetine in PD, showing that this drug (the prototype of multimodal antidepressants) shows superiority with respect to sertraline (an SSRI widely used for the treatment of depression associated with PD) in improving cognitive dysfunction, anhedonia, anxiety, and peripheral markers of inflammation.