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The mitochondrial common deletion in Parkinson's disease and related movement disorders
J Zhang1, T J Montine, M A Smith
1Division of Neuropathology, Vanderbilt University Medical Center, C3321 Medical Center North, Nashville, TN 37232, USA. jing.zhang@mcmail.vanderbilt.edu
Abstract:
The mitochondrial 4977-bp common deletion has been reported in some studies to occur exclusively or with increased frequency in the midbrain of patients with Parkinson's disease (PD). Other studies could not confirm these results; rather, it was suggested that the mitochondrial common deletion is associated with aging in the midbrain and not PD. One possible explanation for these conflicting results is the difficulty in quantifying mitochondrial DNA deletions or mutations in the whole midbrain or substantia nigra (SN) while only a subset of midbrain neurons degenerate in PD. In addition, none of the studies has addressed the cell types with the common deletion within the midbrain. In this study we used in situ hybridization to detect the common deletion in sections of midbrain from patients with PD, multiple system atrophy-parkinsonian type (MSA-P), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), age-matched controls, and individuals of different ages. The results demonstrated that the mitochondrial common deletion accumulated primarily in neurons but not glia in both the SN and other midbrain regions. There was no significant difference in the number or distribution of neurons with the common deletion or the average of the mean densities (AMD) of staining with the common deletion in nigral neurons among patients with PD, MSA-P, PSP, DLB, or age-matched controls. In addition, there was no difference in the number or distribution of neurons with the common deletion in nigral neurons between any age group, although there was a tendency for the common deletion to increase in the non-nigral neurons in older patients. These data indicate that accumulation of the 4977-bp common deletion in mitochondrial DNA in midbrain occurred primarily in neurons, and by this cytological approach, it was not associated with nigral neurodegeneration in the common movement disorders or aging.
Insights
The 4977-bp mitochondrial DNA common deletion accumulates in midbrain neurons, not glia, but is not linked to Parkinson's disease or other parkinsonian disorders. This finding clarifies the role of mitochondrial deletions in neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- The 4977-bp mitochondrial DNA common deletion is implicated in Parkinson's disease (PD) pathogenesis, with conflicting reports on its prevalence in the midbrain.
- Previous studies faced challenges in quantifying mitochondrial DNA deletions in specific midbrain regions and cell types.
Purpose of the Study:
- To investigate the cellular distribution and association of the 4977-bp mitochondrial DNA common deletion in the midbrain of patients with neurodegenerative disorders.
- To determine if the common deletion is linked to Parkinson's disease (PD), multiple system atrophy-parkinsonian type (MSA-P), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), or aging.
Main Methods:
- In situ hybridization was employed to detect the 4977-bp mitochondrial DNA common deletion in midbrain sections.
- Analysis included samples from patients with PD, MSA-P, PSP, DLB, age-matched controls, and individuals across different age groups.
Main Results:
- The mitochondrial common deletion predominantly accumulated in neurons, not glial cells, within both the substantia nigra (SN) and other midbrain regions.
- No significant differences were observed in the number, distribution, or average mean densities of the common deletion in nigral neurons among the studied patient groups or age categories.
- A trend suggested an increase in the common deletion in non-nigral neurons in older individuals.
Conclusions:
- The 4977-bp mitochondrial DNA common deletion primarily accumulates in midbrain neurons.
- This study's cytological approach found no association between the mitochondrial common deletion and nigral neurodegeneration in common movement disorders or aging.