Abstract
Mitochondrial dysfunction within the cell bodies of substantia nigra neurons is prominent in both ageing and Parkinson’s disease. The loss of dopaminergic substantia nigra neurons in Parkinson’s disease is associated with loss of synapses within the striatum, and this may precede neuronal loss. We investigated whether mitochondrial changes previously reported within substantia nigra neurons were also seen within the synapses and axons of these neurons. Using high resolution quantitative fluorescence immunohistochemistry we determined mitochondrial density within remaining dopaminergic axons and synapses, and quantified deficiencies of mitochondrial Complex I and Complex IV in these compartments. In Parkinson’s disease mitochondrial populations were increased within axons and the mitochondria expressed higher levels of key electron transport chain proteins compared to controls. Furthermore we observed synapses which were devoid of mitochondrial proteins in all groups, with a significant reduction in the number of these ‘empty’ synapses in Parkinson’s disease. This suggests that neurons may attempt to maintain mitochondrial populations within remaining axons and synapses in Parkinson’s disease to facilitate continued neural transmission in the presence of neurodegeneration, potentially increasing oxidative damage. This compensatory event may represent a novel target for future restorative therapies in Parkinson’s disease.
Highlights
Parkinson’s disease (PD) is classically associated with a loss of dopaminergic substantia nigra (SN) neurons, it may be the progressive loss of their synapses and axons that leads to the depletion in dopamine neurotransmission.[1]
Changes in synaptic volume in Parkinson’s disease To ascertain whether any structural changes occurred within synapses of substantia nigra neurons we measured the volume of there was a trend for the pre-synaptic volume to be increased in PD and DLB compared to controls, which reached significance in the group analysed for synaptic volume alongside NDUFB8 and porin (PD p = 0.0034; DLB p = 0.005)
As expected, a significant reduction in pre-synaptic dopamine transporter (DAT) positive terminals within the putamen in PD and dementia with Lewy bodies (DLB) cases, compared to controls and AD cases (p ≤ 0.001, n = 6 images analysed per case, Fig. 2a)
Summary
Parkinson’s disease (PD) is classically associated with a loss of dopaminergic substantia nigra (SN) neurons, it may be the progressive loss of their synapses and axons that leads to the depletion in dopamine neurotransmission.[1]. Perhaps the most prominent of these is the alpha-synuclein gene, SNCA.[6] A relatively small and unstructured protein, alpha-synuclein has been proposed to have several functions at the synapse, including modulation of dopamine release and a regulation of ion channels.[7] Alpha-synuclein is capable of interacting with mitochondria and causing their dysfunction,[8] it has been shown that alpha-synuclein can induce mitochondrial dysfunction within SN neurons that precedes neuronal loss.[9,10,11] knock-down of Pink[1], Parkin or DJ-1 causes synaptic dysfunction, with reduced dopamine release and synaptic plasticity in the striatum.[12,13,14,15] LRRK2 has been shown to interact with a number of synaptic proteins to affect the mobilisation of synaptic vesicles,[16] and mutations in LRRK2 cause a reduction in dopamine release into the striatum.[17,18,19]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
