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Neuronal complex I deficiency occurs throughout the Parkinson's disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
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.
- Subjects :
- 0301 basic medicine
Male
Parkinson's disease
Mitochondrial Diseases
Respiratory chain
Complex I
Mitochondria
Parkinsonism
Substantia nigra
2734
Neurology (clinical)
Cellular and Molecular Neuroscience
Mitochondrion
0302 clinical medicine
80 and over
Prospective Studies
Aged, 80 and over
Neurons
education.field_of_study
Neurodegeneration
Brain
Parkinson Disease
Middle Aged
Mitochondrial
alpha-Synuclein
Female
Mitochondrial DNA
Population
Biology
DNA, Mitochondrial
Protein Aggregation, Pathological
Pathology and Forensic Medicine
03 medical and health sciences
Pathological
medicine
Humans
education
Aged
Electron Transport Complex I
DNA
DNA Damage
Nerve Degeneration
medicine.disease
Protein Aggregation
030104 developmental biology
nervous system
Neuroscience
030217 neurology & neurosurgery
Subjects
Details
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....9dfce516657dd075bfb4ecd79d84a352
- Full Text :
- https://doi.org/10.17863/cam.21337