Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

Abstract

Mitochondrial complex I deficiency occurs in the substantia nigra of individuals with Parkinson's disease. It is generally believed that this phenomenon is caused by accumulating mitochondrial DNA damage in neurons and that it contributes to the process of neurodegeneration. We hypothesized that if these theories are correct, complex I deficiency should extend beyond the substantia nigra to other affected brain regions in Parkinson's disease and correlate tightly with neuronal mitochondrial DNA damage. To test our hypothesis, we employed a combination of semiquantitative immunohistochemical analyses, Western blot and activity measurements, to assess complex I quantity and function in multiple brain regions from an extensively characterized population-based cohort of idiopathic Parkinson's disease (n = 18) and gender and age matched healthy controls (n = 11). Mitochondrial DNA was assessed in single neurons from the same areas by real-time PCR. Immunohistochemistry showed that neuronal complex I deficiency occurs throughout the Parkinson's disease brain, including areas spared by the neurodegenerative process such as the cerebellum. Activity measurements in brain homogenate confirmed a moderate decrease of complex I function, whereas Western blot was less sensitive, detecting only a mild reduction, which did not reach statistical significance at the group level. With the exception of the substantia nigra, neuronal complex I loss showed no correlation with the load of somatic mitochondrial DNA damage. Interestingly, α-synuclein aggregation was less common in complex I deficient neurons in the substantia nigra. We show that neuronal complex I deficiency is a widespread phenomenon in the Parkinson's disease brain which, contrary to mainstream theory, does not follow the anatomical distribution of neurodegeneration and is not associated with the neuronal load of mitochondrial DNA mutation. Our findings suggest that complex I deficiency in Parkinson's disease can occur independently of mitochondrial DNA damage and may not have a pathogenic role in the neurodegenerative process.

Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition

“…Moreover, we observed an attenuation in the down-regulation of mitochondrial pathways, including the respiratory chain and oxidative phosphorylation, which are among the most consistent transcriptomic signatures in PD [2,4,19,21,[25][26][27][28]. The loss of transcriptional signal in these pathways is intriguing, because there is compelling evidence that decreased complex I protein levels occur in PD neurons [29]. Our results suggest that the previously reported transcriptional down-regulation of the respiratory chain is at least partly driven by altered cellular composition (due to decreased number of neurons which highly express these genes) and may therefore not be the sole mechanism by which neuronal complex I deficiency occurs in PD.…”

Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition

“…Complete results are provided in Additional file 6 9,19,20,29,42,55,57]. The loss of transcriptional signal in these pathways is intriguing, because there is compelling evidence that decreased complex I protein levels occur in PD neurons [23]. Our results suggest that the previously reported transcriptional down-regulation of the respiratory chain is at least partly driven by altered cellular composition (due to decreased number of neurons which highly express these genes) and may therefore not be the sole mechanism by which neuronal complex I deficiency occurs in PD.…”

Rare genetic variation in mitochondrial pathways influences the risk for Parkinson's disease

“…Mutations in most of the genes causing familial PD, including SNCA , LRRK2 , PINK1, PRKN , PARK7 ( DJ‐1 ), and VPS35 , have been shown to disrupt mitochondrial quality control. Moreover, impaired mitochondrial DNA (mtDNA) maintenance and widespread respiratory chain dysfunction occur in the brains of individuals with idiopathic PD. The molecular etiology underlying mitochondrial impairment in idiopathic PD remains, however, unresolved.…”