New synaptic and molecular targets for neuroprotection in Parkinson's disease

Abstract

The defining anatomical feature of Parkinson's disease (PD) is the degeneration of substantia nigra pars compacta (SNc) neurons, resulting in striatal dopamine (DA) deficiency and in the subsequent alteration of basal ganglia physiology. Treatments targeting the dopaminergic system alleviate PD symptoms but are not able to slow the neurodegenerative process that underlies PD progression. The nucleus striatum comprises a complex network of projecting neurons and interneurons that integrates different neural signals to modulate the activity of the basal ganglia circuitry. In this review we describe new potential molecular and synaptic striatal targets for the development of both symptomatic and neuroprotective strategies for PD. In particular, we focus on the interaction between adenosine A2A receptors and dopamine D2 receptors, on the role of a correct assembly of NMDA receptors, and on the sGC/cGMP/PKG pathway. Moreover, we also discuss the possibility to target the cell death program parthanatos and the kinase LRRK2 in order to develop new putative neuroprotective agents for PD acting on dopaminergic nigral neurons as well as on other basal ganglia structures.

FIG. 1

Striatal D2/A2A interaction on cholinergic interneurons modulates both D1- and D2-receptor-expressing medium spiny neuron (MSN) activity. In the nucleus striatum activation of both dopamine D2 and adenosine A2A receptors decreases the activation of cholinergic interneurons and the release of acetylcholine. The subsequent lowering of the M1 muscarinic receptor tone favors the disinhibition of Cav1.3 Ca²⁺ channels, the increase in intracellular calcium concentration, and finally the production and release of endocannabinoids (ECBs). ECBs travel across the synapse and activate presynaptic CB1 receptors, causing reduced glutamate release, thus modulating excitatory synaptic transmission onto both (left) D1- and (right) D2-receptor-expressing medium spiny neurons (Ach, acetylcholine; DA, dopamine; Glu, glutamate; GluRs, glutamate receptors).

FIG. 2

The importance of physiologic NMDA receptor subunit balance for motor activity and striatal synaptic plasticity. In physiologic condition (upper), a correct balance between NR2A and NR2B subunits of the NMDA receptor is associated with normal motor activity and with the ability of excitatory striatal synapses to induce long-term potentiation (LTP) after high-frequency stimulation (HFS) of corticostriatal fibers. In experimental models of early Parkinson’s disease (middle), development of motor impairment is associated with an increase of the synaptic NR2A/NR2B subunit ratio and with altered expression of synaptic LTP after HFS. The treatment with TAT2A peptides (lower) targeting MAGUK–NR2A subunit interaction is able to ameliorate the clinical symptoms of the experimental disease, to normalize the synaptic NR2A/NR2B synaptic ratio, and to restore thesynapses’ ability to express LTP after HFS (MAGUK, membrane-associated guanylate kinases).

FIG. 3

Inhibition of phosphodiesterases rescues striatal long-term depression (LTD) in experimental models of Parkinson’s disease (PD). Nitric oxide (NO) released by nitric oxide synthase (NOS)–positive interneurons activates soluble guanylyl cyclases (sGC), which stimulates the synthesis of the second-messenger cGMP, which, in turn, facilitates striatal LTD induction. Experimental models of PD are associated with the loss of LTD at glutamatergic striatal synapses onto spiny neurons. Treatment with inhibitors of phosphodiesterases (PDEs) is able to restore LTD induction at striatal synapses and to ameliorate motor performances (cGMP, cyclic GMP; DA, dopamine; DARPP32, dopamine and cAMP-regulated phosphoprotein 32 kDa; Glu, glutamate; MSN, medium spiny neuron; PDE, phosphodiesterases; PDE-inh, inhibitors of phosphodiesterases; PKG, protein kinase G).