title: 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.
authors.affiliation: Clinical Neurology, University of Perugia, Perugia, Italy. calabre@unipg.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Di Filippo
authors.forename: Antongiulio
authors.initials: A
authors.lastname: Gallina
authors.forename: Yingfei
authors.initials: Y
authors.lastname: Wang
authors.forename: Jeannette N
authors.initials: JN
authors.lastname: Stankowski
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
mesh_terms: D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects* / Q000473:pathology
chemical_list: D018696:Neuroprotective Agents; D043705:Receptor, Adenosine A2A; D011954:Receptors, Dopamine; D016194:Receptors, N-Methyl-D-Aspartate; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases