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.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting 1.8% of the population above the age of 65 years [11]
Quantification confirmed that individuals with PD had decreased neuronal complex I staining in all areas, whereas complexes II–V stained similar to healthy controls (Fig. 2b)
We show that mitochondrial complex I deficiency is not limited to the SNc and other areas affected by neurodegeneration, but is a widespread phenomenon affecting neurons throughout the brain of individuals with PD
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting 1.8% of the population above the age of 65 years [11]. It is characterized by progressive motor dysfunction including bradykinesia, rigidity, resting tremor and postural instability. A number of non-motor symptoms occur, including autonomic dysfunction, dementia, depression and anxiety. The pathological hallmark of PD is the degeneration of the dopaminergic neurons in the pars compacta of the substantia nigra (SNc) in the presence of α-synuclein immunoreactive neuronal inclusions collectively termed Lewy pathology. Other affected areas comprise multiple brainstem and cholinergic nuclei, the hippocampus and the neocortex. Spared regions include the striatum, cerebellum, thalamus, red nucleus and the pontine nuclei [12]
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