Investigating complex I deficiency in Purkinje cells and synapses in patients with mitochondrial disease. (30th September 2015)

• Record Type: Journal Article
• Authors: Chrysostomou, Alexia; Grady, John P.; Laude, Alex; Taylor, Robert W.; Turnbull, Doug M.; Lax, Nichola Z.
• Is Part Of: Neuropathology & applied neurobiology. Volume 42:Number 5(2016)
• Page Start: 477
• Page End: 492
• Publication Date: 2015-09-30
• Subjects: ataxia -- mitochondrial disease -- mitochondrial DNA -- Purkinje cells -- respiratory chain deficiency -- synapses; Nervous system -- Diseases -- Pathology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/nan.12282
• Languages: English
• ISSNs: 0305-1846

Abstract

Abstract : Aims: Cerebellar ataxia is common in patients with mitochondrial disease, and despite previous neuropathological investigations demonstrating vulnerability of the olivocerebellar pathway in patients with mitochondrial disease, the exact neurodegenerative mechanisms are still not clear. We use quantitative quadruple immunofluorescence to enable precise quantification of mitochondrial respiratory chain protein expression in Purkinje cell bodies and their synaptic terminals in the dentate nucleus. Methods: We investigated NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 13 protein expression in 12 clinically and genetically defined patients with mitochondrial disease and ataxia and 10 age‐matched controls. Molecular genetic analysis was performed to determine heteroplasmy levels of mutated mitochondrial DNA in Purkinje cell bodies and inhibitory synapses. Results: Our data reveal that complex I deficiency is present in both Purkinje cell bodies and their inhibitory synapses which surround dentate nucleus neurons. Inhibitory synapses are fewer and enlarged in patients which could represent a compensatory mechanism. Mitochondrial DNA heteroplasmy demonstrated similarly high levels of mutated mitochondrial DNA in cell bodies and synapses. Conclusions: This is the first study to use a validated quantitative immunofluorescence technique to determine complex I expression in neurons and presynaptic terminals, evaluating the distribution of respiratory chain deficiencies and assessing the degree of morphological abnormalities affecting synapses. Respiratory chain deficiencies detected in Purkinje cell bodies and their synapses and structural synaptic changes are likely to contribute to altered cerebellar circuitry and progression of ataxia. Abstract : Quantitative quadruple immunofluorescence demonstrates Purkinje cell complex 1 deficiency in mitochondrial disease, furthering our understanding of neurodegenerative mechanisms in these complex disorders.