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Altered cortical innervation | |
(i) ↓ Dopamine (nigrostriatal and mesocortical pathways): indirect and direct pathways | |
(ii) ↓ Noradrenaline (locus ceruleus) | |
(iii) ↓ Serotonine (raphe nuclei) | |
(iv) ↓ Acetylcholine (nuclei of the basal forebrain) | |
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Synaptic pathology | |
(i) ↑ Tau phosphorylation in synaptic fractions | |
(ii) ↑ α-synuclein phosphorylation in synaptic fractions | |
(iii) Small α-synuclein aggregates at the synapses | |
Altered α -synuclein and α-synuclein interactions | |
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(i) Oxidation and phosphorylation of α-synuclein | |
(ii) Abnormal synuclein interactions with | |
(a) rab3a: possible altered synaptic traffic | |
(b) rab5: possible altered endocytosis | |
(c) rab8: possible altered transport | |
(d) PLCβ: altered mGluR1 signalling | |
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Altered mitochondria | |
(i) ↑ Mitochondrial mass | |
(ii) ↓ Complex I of the respiratory chain | |
(iii) ↓ Mitochondrial O2 uptake | |
(iv) Oxidative damage of subunits of mitochondrial complex I and DJ1 | |
(v) (altered DJ1, PINK1, LRRK2, and Htr2 in familial PD) | |
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Increased oxidative damage | |
(i) ↑ Lipoxidative and glycoxidative damage of proteins and oxidative damage of DNA | |
(ii) ↑ Oxidative damage of proteins linked with glycolysis and energy metabolism | |
(iii) ↑ Oxidative damage of superoxide dismutase 2 | |
(iv) ↑ Oxidative damage of β-synuclein, α-synuclein, cytoskeletal proteins and UCHL1 | |
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Altered composition of membrane lipids in the grey matter | |
(i) Total homogenates | |
(ii) Lipid rafts: ↑ viscosity | |
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Late, secondary events | |
(i) Synaptic loss | |
(ii) Lewy bodies and neurites | |
(iii) Neuronal death | |
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