What causes cell death in Parkinson's disease?

Abstract

Currently, there is no proven neuroprotective or neurorestorative therapy for Parkinson's disease (PD). Several advances in the genetics of PD have created an opportunity to develop mechanistic-based therapies that hold particular promise for identifying agents that slow and even halt the progression of PD, as well as restore function. Here we review many of the advances in the last decade regarding the identification of new targets for the treatment of PD based on understanding the molecular mechanisms of how mutations in genes linked to PD cause neurodegeneration.

Figure 1

Molecular Mechanisms of Neurodegeneration in PD. There are multiple potential pathways of cell death in PD. It is unclear at the present time whether these pathways converge to one overarching central cell death mechanism in PD or whether they are independently and distinctly involved in different forms of genetic and sporadic PD. On the left are potential mechanisms and therapeutic targets for sporadic PD. Central to sporadic PD is mitochondrial complex I deficiency, which is modeled by MPTP and other complex I inhibitors. MPTP is converted by monoamine oxidase B (MAO_B) to MPP⁺ where it is concentrated in dopamine neurons due to its high affinity for the DA transporter (DAT) followed by transport and concentration into the mitochondria due to its positive charge. Once in the mitochondria, MPP⁺ poisons the mitochondria by inhibiting complex I. Selegiline and rasagiline were initially used as neuroprotective agents due their inhibition of MAO_B, but it is now thought that they may actually inhibit GAPDH-dependent-cell death pathways downstream of complex I inhibition. Calcium channel antagonists of the dihydropyridine class may rejuvenate DA neurons to the point where they use sodium channels for their characteristic pacing, thus rendering them resistance to toxic effects of complex I inhibition. Co-enzyme Q10 and creatine have neuroprotective properties in animal models of PD through augmenting the function of mitochondria. Complex I inhibition leads to cell death through classic apoptotic pathways, endoplasmic reticulum (ER) stress as well as neuronal nitric oxide synthase (nNOS) activation, DNA damage and poly (ADP-ribose) polymerase (PARP) activation. Accompanying derangements in mitochondrial complex I is the subsequent activation of microglia. Strategies aimed at reducing the inflammatory process in PD holds particular promise. On the right are potential therapeutic opportunities for familial PD. DJ-1 appears to function in controlling the level of reactive oxygen species (ROS). Reducing oxidative stress and/or restoring DJ-1 function may be protective. PINK1 is a mitochondrial kinase and disruption of PINK1 may lead to alterations in the function of TRAP1 and HtrA2 setting in motion cell death pathways. Thus, strategies aimed at inhibiting TRAP1 and/or HtrA2 as well as enhancing PINK1 may be beneficial. Parkin is an E3 ubiquitin (Ub) ligase and strategies aimed at maintaining its catalytic activity are particularly attractive, as well as, lowering the burden of toxic substrates such as aminoacyl-tRNA synthetase (ARS) interacting multifunctional protein type 2 (AIMP2) and the Far Upstream Element-binding Protein-1 (FBP-1), which are degraded by the ubiquitin proteasome system (UPS) in a parkin-dependent manner. S-nitrosylation (SNO) of parkin inhibits its activity and interfering with this process may also be protective. PINK1 and parkin appear to function in a common genetic pathway with PINK1 acting upstream of parkin, thus maintaining parkin function will in theory inhibit PINK1 dependent cell death pathways. LRRK2 kinase and/or GTPase inhibitors may be beneficial against cell death due to LRRK2 mutations. Reducing ROS and reactive nitrogen species (RNS), modulating α-synuclein (α-syn) phosphorylation (PO₄), reducing α-synuclein levels through RNAi or immunotherapy, reducing α-synuclein oligomerization, inhibiting α-synuclein cleavage or enhancing the degradation of α-synuclein through inhibition of SIRT2 are potential targets to reduce neurodegeneration by derangements in α-synuclein.