Loss of mortalin function in PD – supporting the mitochondrial pathway of neurodegeneration.

Dysfunctional mitochondria have been early implicated in the neurodegenerative process leading to idiopathic Parkinson’s disease (PD) based on biochemical and immunohistochemical findings in affected brain regions of PD patients. The identification of genetic causes of PD during the last decade allowed for the first time to study disease-relevant molecular signaling cascades of neurodegeneration. Based on rare families with autosomal recessively inherited forms of early onset PD, first genes were identified that encode proteins that are critical for the maintenance of mitochondrial function and morphology and therefore contribute to the mitochondrial phenotype of PD. For instance, loss of function mutations in the DJ-1 gene cause impaired mitochondrial respiration with accumulation of free oxygen species, disruption of the mitochondrial energy metabolism and characteristic morphological changes of these organelles. Interestingly, the mitochondrial chaperone protein mortalin was identified as a DJ-1-interacting protein by several groups. Subsequent genetic studies in large cohorts of PD patients revealed first loss of function mutations as risk factors for PD. These disease-associated mortalin variants showed effects on mitochondrial dynamics that paralleled the phenotype observed upon lack of DJ-1 in different in vitro and ex vivo models. These results provided first evidence for a mitochondrial matrix chaperone involved in neuronal cell death in PD and strengthen the relevance of a mitochondrial endophenotype in PD. Therefore, functional studies of mortalin allow to dissect the signaling pathways involved in mitochondrial causes of neurodegeneration in PD and may provide new targets for therapeutic approaches in PD.