Cross-talk between mitochondria and proteasome in Parkinson's disease pathogenesis

Abstract

Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder, characterized by the selective loss of nigrostriatal dopaminergic neurons, and the presence of intracellular insoluble proteinaceous inclusions, known as Lewy Bodies. Although PD etiopathogenesis remains elusive, the leading hypothesis for the death of specific groups of neurons establishes that mitochondrial dysfunction, alterations in the ubiquitin-proteasomal system (UPS), and oxidative stress are major events that act synergistically causing this devastating disease. In this review we will focus on mitochondrial impairment and its implications on proteasomal function and alpha-synuclein aggregation. We will address the role of mitochondria and proteasome cross-talk in the neuronal loss that leads to PD and discuss how this knowledge might further improve patient therapy.

Keywords: Parkinson's disease; alpha-synuclein; dopamine; mitochondria; proteasome.

Figure 1

Major proposed functions of alpha-synuclein in the cell.

Figure 2

The misfolding process of alpha-synuclein may result from either genetic mutations, responsible for familial forms of the disease, or post-translational changes to the protein mainly due to oxidative/nitrosative stress, which is more likely to be related to sporadic forms of PD. Two main events are related to ROS/RNS formation: (1) excessive Ca²⁺ influx due to activation of NMDA-type glutamate receptors in nervous system, with activation of neuronal NO synthase as well, as the generation of ROS and (2) Dysfunctional mitochondrial respiration that is one of the major sources of ROS in the cell. Excessive ROS/RNS formation by these two processes may induce UPS impairment, thus resulting in protein aggregation. This may explain the etiology of the two PD neuropathological hallmarks, LBs formation and neuronal death.

Figure 3

Mitochondrial and proteasomal cross-talk in PD pathogenesis. The four mitochondrial main functions are (1) ATP production (2) regulation of calcium homeostasis (3) oxidative stress and (4) apoptotic cell death mediation. Proteasome is a major protein degradation cell complex. Reduction in mitochondrial cx I activity in LOPD and the acute model of PD (MPP⁺) inhibit proteasome activity, as it actually happens in LOPD and with aging. Also in PARK6 (PINK1 mutation - EOPD) there is mitochondrial function compromise and therefore proteasome impairment. However, recent and preliminary results shown an up-regulation of proteasomal activity in ndufa knockdown cells. In the opposite way of this two ways crosstalk, lactacystin and/or mutations in genes that code PINK1 (PARK6), parkin (PARK2) and DJ-1 (PARK7) may interfere with the function of the ubiquitin E3 ligase activity complex, inducing alpha-synuclein aggregation and mitochondrial-mediated apoptosis. Accumulation of alpha-synuclein oligomers potentiates proteasome impairment in a vicious cycle. Also described in the figure are parkin function of induce autophagy in dysfunctional mitochondria and UCHL-1 deubiquitinating activity, impaired in PARK2 and PARK5, respectively.