Alpha synuclein has been linked to both sporadic and familial forms of Parkinson’s disease (PD) and is the most abundant protein in Lewy bodies a hallmark of Parkinson’s disease. The function of this protein and the molecular mechanisms underlying its toxicity are still unclear, but many studies have suggested that the mechanism of α-synuclein toxicity involves alterations to mitochondrial function. Here we expressed human α-synuclein and two PD-causing α-synuclein mutant proteins (with a point mutation, A53T, and a C-terminal 20 amino acid truncation) in the eukaryotic model Dictyostelium discoideum. Mitochondrial disease has been well studied in D. discoideum and, unlike in mammals, mitochondrial dysfunction results in a clear set of defective phenotypes. These defective phenotypes are caused by the chronic hyperactivation of the cellular energy sensor, AMP-activated protein kinase (AMPK). Expression of α-synuclein wild type and mutant forms was toxic to the cells and mitochondrial function was dysregulated. Some but not all of the defective phenotypes could be rescued by down regulation of AMPK revealing both AMPK-dependent and -independent mechanisms. Importantly, we also show that the C-terminus of α-synuclein is required and sufficient for the localisation of the protein to the cell cortex in D. discoideum.

The unicellular slime mould Dictyostelium discoideum is a valuable eukaryotic model organism in the study of mitochondrial biology and disease. As a member of the Amoebozoa, a sister clade to the animals and fungi, Dictyostelium mitochondrial biology shares commonalities with these organisms, but also exhibits some features of plants. As such it has made significant contributions to the study of eukaryotic mitochondrial biology. This review provides an overview of the advances in mitochondrial biology made by the study of Dictyostelium and examines several examples where Dictyostelium has and will contribute to the understanding of mitochondrial disease. The study of Dictyostelium's mitochondrial biology has contributed to the understanding of mitochondrial genetics, transcription, protein import, respiration, morphology and trafficking, and the role of mitochondria in cellular differentiation. Dictyostelium is also proving to be a versatile model organism in the study both of classical mitochondrial disease e.g. Leigh syndrome, and in mitochondria-associated neurodegenerative diseases like Parkinson's disease. The study of mitochondrial diseases presents a unique challenge due to the cryptic nature of their genotypephenotype relationship. The use of Dictyostelium can contribute to resolving this problem by providing a genetically tractable, haploid eukaryotic organism with a suite of readily characterised phenotype readouts of cellular signalling pathways. Dictyostelium has provided insight into the signalling pathways involved in multiple neurodegenerative diseases and will continue to provide a significant contribution to the understanding of mitochondrial biology and disease.

Mitochondrial Complex II is composed of four core subunits and mutations to any of the subunits result in lowered Complex II activity. Surprisingly, although mutations in any of the subunits can yield similar clinical outcomes, there are distinct differences in the patterns of clinical disease most commonly associated with mutations in different subunits. Thus, mutations to the SdhA subunit most often result in mitochondrial disease phenotypes, whilst mutations to the other subunits SdhB-D more commonly result in tumour formation. The reason the clinical outcomes are so different is unknown. Here, we individually antisense-inhibited three of the Complex II subunits, SdhA, SdhB or SdhC, in the simple model organism Dictyostelium discoideum. Whilst SdhB and SdhC knockdown resulted in growth defects on bacterial lawns, antisense inhibition of SdhA expression resulted in a different pattern of phenotypic defects, including impairments of growth in liquid medium, enhanced intracellular proliferation of the bacterial pathogen Legionella pneumophila and phagocytosis. Knockdown of the individual subunits also produced different abnormalities in mitochondrial function with only SdhA knockdown resulting in broad mitochondrial dysfunction. Furthermore, these defects were shown to be mediated by the chronic activation of the cellular energy sensor AMP-activated protein kinase. Our results are in agreement with a role for loss of function of SdhA but not the other Complex II subunits in impairing mitochondrial oxidative phosphorylation and they suggest a role for AMP-activated protein kinase in mediating the cytopathological outcomes.