Mitochondrial Dysfunction in Parkinson's Disease-Cause or Consequence?

Abstract

James Parkinson first described the motor symptoms of the disease that took his name over 200 years ago. While our knowledge of many of the changes that occur in this condition has increased, it is still unknown what causes this neurodegeneration and why it only affects some individuals with advancing age. Here we review current literature to discuss whether the mitochondrial dysfunction we have detected in Parkinson's disease is a pathogenic cause of neuronal loss or whether it is itself a consequence of dysfunction in other pathways. We examine research data from cases of idiopathic Parkinson's with that from model systems and individuals with familial forms of the disease. Furthermore, we include data from healthy aged individuals to highlight that many of the changes described are also present with advancing age, though not normally in the presence of severe neurodegeneration. While a definitive answer to this question may still be just out of reach, it is clear that mitochondrial dysfunction sits prominently at the centre of the disease pathway that leads to catastrophic neuronal loss in those affected by this disease.

Keywords: Parkinson’s disease; ageing; mitochondria; neurodegenerative disease.

Figure 1

Mitochondrial respiratory chain (RC) deficiency in substantia nigra (SN) neurons of an individual with Parkinson’s disease (PD). Immunofluorescent images demonstrating SN neurons with normal Complex I (CI) and Complex IV (CIV) expression, Complex I deficiency and normal Complex IV expression, and deficiency of both Complex I and Complex IV. Scale bar, 20 µm.

Figure 2

Schematic presentation of mitochondrial involvement in the pathogenesis of Parkinson’s disease (PD). This diagram serves to highlight the complex links between the changes in mitochondrial homeostasis, turnover, quality control and trafficking in cases of PD. These mitochondrial alternations are also intricately associated with the ageing process and impairments of the ubiquitin protease system that are attributed to Lewy body pathology. Lines with dots represent interactive effects, lines with arrows represent regulatory effects. Genes associated with familial PD are shown in blue, while we have also highlighted other proteins and toxins, recently been associated with PD, which impact on mitochondrial function. MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; VPS35: vacuolar protein sorting 35; CHCHD2: coiled-coil-helix-coiled-coil-helix domain containing 2; TFAM: mitochondrial transcription factor A; AMPK: AMP-activated protein kinase; PGC-1α: peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α; NRF: nuclear respiratory factors; TFB2M: dimethyladenosine transferase 2; DRP1: dynamin-1-like protein; MFN: mitofusin; LRRK2: Leucine-rich repeat kinase 2; PINK1: phosphatase and tensin homolog (PTEN)-induced putative kinase 1; GBA: lysosomal enzyme glucocerebrosidase; MIRO: mitochondrial Rho GTPase1; ∆Ѱm: mitochondrial membrane potential; ROS: reactive oxygen species; mtDNA: mitochondrial DNA; UPR^mt: the mitochondrial unfolded protein response.