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- 1. Missing pieces in the Parkinson’s disease puzzle 1
- 2. Why are SNc cells especially vulnerable? 1. Dopamine Dopamine metabolism Auto-oxidation Dopamine and alpha-synoclein 2. neuromelanin 3. less capacity for calcium buffering 4. increased reliance on L-type calcium channels 5. expression of specific transcription 2
- 3. 3
- 4. α-synuclein 140 amino acids the function is not well understood maintaining a supply of synaptic vesicles in presynaptic terminals by clustering synaptic vesicles. It may also help regulate the release of dopamine, 4
- 5. Dopamine and α- synuclein Dopamine toxicity in the SNc is reduced in α-synuclein– knockout mice critical interaction between the cellular concentrations of α-synuclein and dopamine and the inhibition (by dopamine) of chaperone- mediated autophagy in SNc neurons 5
- 6. Neuromelanin (NM) is a dark pigment found in the brain which is structurally related to melanin. It is a polymer of 5,6-dihydroxyindole monomers. 6
- 7. Role of neuromelanin The most obvious difference in relation to the regional pattern of cell loss in the SNc occurs in the neuromelanin-containing neurons, which are more susceptible than neuromelanin-free dopamine neurons However, vulnerability within the ventrolateral SNc is unrelated to the amount of neuromelanin per neuron Patients with Parkinson's disease had 50% the amount of neuromelanin in the substantia nigra as compared to similar patients of their same age, but without Parkinson's may be partly due to oxidative stress 7
- 8. 8
- 9. 9
- 10. Other factors less capacity for calcium buffering increased reliance on L-type calcium channels expression of specific transcription factors that regulate cell fate and survival 10
- 11. less capacity for calcium buffering Calpain is a ubiquitous calcium-sensitive protease essential for normal physiologic neuronal function mitochondrial-mediated-calcium homeostasis alterations may lead to its pathologic activation that jeopardizes neuronal structure and function 11
- 12. dysfunctional mitochondria increases cytosolic calcium, thereby, inducing calpain activation calpain-1 overactivation in our mitochondrial-deficient cells promote caspase-3 activation 12
- 13. increased reliance on L-type calcium channels unusual reliance of these neurons on L-type Ca(v)1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought The reliance on these channels increases with age, blocking Ca(v)1.3 Ca2+ channels in adult neurons a new strategy that could slow or stop the progression of the diseas 13
- 14. expression of specific transcription factors Studies of transcription factors, such as Nurr1, Pitx3, Engrailed-1/2, and Lmx1a/b, have not only revealed importance of these genes during development, but also roles in the long-term survival and maintenance of these neurons. 14
- 15. Does neurodegeneration begin in the SNc? In people with Parkinson’s disease who die after a relatively short disease (<5 years), early cell loss occurs in two places SNc resupplementary motor cortex 15
- 16. The supplementary motor area (SMA) is a part of the primate cerebral cortex that contributes to the control of movement. It is located on the midline surface of the hemisphere just in front of (anterior to) the primary motor cortex leg representation. 16
- 17. The time course of cell loss has been studied in the SNc most of the cell loss occurs in a 5–10-year preclinical period during 17
- 18. Which mechanisms underlie progressive SNc cell loss? The motor features of Parkinson’s disease are mainly related to loss of striatal dopamine secondary to degeneration of dopamine neurons in the SNc 18
- 19. Striatal dopamine innervation assessed by 18F-dopa positron emission tomography. 19
- 20. What underlies the nondopaminergic features of the disease? are still hotly debated Affected nondopamine neurons include • monoaminergic cells in the locus coeruleusand raphe nuclei • cholinergic cells associated with cognitive deficits areas which may be related to gait problems • hypocretin cells in the hypothalamus which likely mediate the sleep disorders seen in Parkinson’s disease 30–50% of these nondopamine cells have been lost by end-stage Parkinson’s disease 20
- 21. pathological model proposed by Braak and colleagues reflects the stepwise progression of Lewy body pathology in the brain. These authors have suggested a caudorostral gradient of Lewy body formation from the lower brainstem to the neocortex 21
- 22. neocortex a part of the cerebral cortex concerned with sight and hearing in mammals, regarded as the most recently evolved part of the cortex 22
- 23. 23
- 24. This suggests that once the disease has started, there is a single progression wave, and that the onset of dementia, generally late in the course of Parkinson’s disease, is due to cortical Lewy bodies. 24
- 25. Indeed, in people with slow disease progression, dementia usually occurs late, and individuals with dementia show a high incidence of limbic and neocortical Lewy bodies 25
- 26. 26
- 27. Overall, the current data support the existence of two phenomena that affect disease progression 1. cell loss 2. increase in the abnormal accumulation of Lewy bodies The second mechanism seems to be dominant in patients with late-onset disease 27
Editor's Notes
- An imbalance between the production and elimination of reactive oxygen species could contribute to the pathogenesis of Parkinson's disease and other neurodegenerative disorders. a | Metabolism of dopamine (DA) leads to the formation of several cytotoxic molecules, including superoxide anions (O2-), dopamine–quinone species (SQ) and hydroxyl radicals (OH). Dopamine breakdown can occur spontaneously in the presence of iron, or can be catalysed by monoamine oxidase (MAO) in a reaction that generates hydrogen peroxide (H2O2). Even though hydrogen peroxide is not damaging to cells, the formation of hydroxyl radicals by the Fenton reaction can lead to cytotoxicity. Normally, cells scavenge these deleterious molecules using several antioxidant systems. For instance, glutathione (GSH) peroxidase detoxifies hydrogen peroxide using reduced glutathione. Oxidized glutathione (GSSG) can be reduced by GSSG reductase and reused. GSH-S-transferase converts electrophilic centres of various potentially toxic compounds to thioether bonds. Superoxide dismutase converts superoxide to hydrogen peroxide. Catalase, in turn, converts hydrogen peroxide to molecular oxygen and water. b | In Parkinson's disease, however, an abnormal increase in the production of reactive oxygen species might tilt the balance between production and elimination, leading to enhanced oxidative stress. DOPAC, 3,4-dihydroxyphenylacetic acid.
- Dopamine (DA) required for neuronal signalling is vesicle bound and redox inert; when DA is released from the vesicle into the cytoplasm it is able to coordinate Fe and undergo redox reactions that result in the formation of neuromelanin (NM) and reactive oxygen species (ROS). Neuromelanin will also coordinate Fe and produce ROS. The equilibrium between vesicle bound dopamine and cytoplasmic dopamine is regulated by alpha-synuclein; mutations in this protein shift the dopamine equilibrium in favour of the cytoplasm. In the presence of Fe and under conditions of oxidative stress alpha-synuclein will aggregate and form deposits. MPP, 1-methyl-4-phenyl pyridine.
- Some motor areas in the human cortex. The supplementary motor area is shown in pink. Image by: Paskari
- Figure 2 Striatal dopamine innervation assessed by 18F-dopa positron emission tomography. (a) Mean control values for eight control subjects shows high uptake (highest value in white) in the striatum. (b) Subject with Parkinson’s disease (right) featuring slowness and rigidity on the right limbs but minimal signs on the left limbs. Uptake is markedly reduced (70% below normal) in the left posterior putamen and reduced to a minor extent in the anterior putamen and caudate of the left hemisphere. (c) SPM2-based analysis (yellow represents the largest statistical difference and red the smallest one), showing the difference in uptake between a and b to highlight the caudorostral pattern of denervation. The statistical map is rendered over the MRI for anatomical localization
- Fig. 4. Progression of PD-related intraneuronal pathology. The pathological process targets specific subcortical and cortical induction sites (a–i). (a and e) Lesions initially occur in the dorsal IX/X motor nucleus and frequently (a and d) in the anterior olfactory nucleus as well. Thereafter, less susceptible brain structures gradually become involved (see white arrows). The pathology in the anterior olfactory nucleus expands less readily into related areas than that evolving in the brain stem. The brain stem pathology takes an upward course (see white arrows). (a–d, g–h) Cortical involvement follows, commencing with the anteromedial temporal mesocortex (tr and er in g and h). From there, the neocortex succumbs, beginning with high order sensory association and prefrontal areas. First order sensory association/premotor areas and, thereafter, primary sensory and motor fields follow suit. In (a–h), the gradual decrease in shading intensity is intended to represent the topographical expansion of the lesions during the course of the disease. Simplified diagram (i) showing the topographic expansion of the lesions (from left to right: dm to fc) and, simultaneously, the growing severity on the part of the overall pathology (from top to bottom: stages 1–6). With the addition of further predilection sites, the pathology in the previously involved regions increases. List of abbreviations: ab, accessory basal nucleus of the amygdala; ac, accessory cortical nucleus of the amygdala; ai, agranular and dysgranular insular cortex; ba, basal nucleus of the amygdala; bn, basal nucleus of Meynert; ca, caudate nucleus; CA1, first sector of the Ammon’s horn; CA2, second sector of the Ammon’s horn; cc, corpus callosum; ce, central nucleus of the amygdala; cl, claustrum; cm, centromedian nucleus of the thalamus; co, coeruleus–subcoeruleus complex; cr, nucleus raphes centralis; db, interstitial nucleus of the diagonal band; dm, dorsal motor nucleus of the glossopharyngeal and vagal nerves; do, dorsomedial nucleus of the hypothalamus; dr, nucleus raphes dorsalis; dv, dorsal nuclear complex of the glossopharyngeal and vagal nerves containing melanized projection neurons; en, entorhinal region; er, ectorhinal region (mesocortex); fo, fornix; fc, first order sensory association areas, premotor areas, as well as primary sensory and motor fields; gi, granular insular cortex; gr, granular nucleus of the amygdala; hc, high order sensory association areas and prefrontal fields; hn, motor nucleus of the hypoglossal nerve; in, infundibular nucleus of the hypothalamus; iz, intermediate reticular zone; la, lateral nucleus of the amygdala; ld, laterodorsal nucleus of the thalamus; lg, lateral geniculate body of the thalamus; lt, lateral nuclei of the thalamus; me, medial nucleus of the amygdala; ml, medial lemniscus; mf, medial longitudinal fascicle; mc, anteromedial temporal mesocortex; ot, optic tract; pa, paraventricular nucleus of the thalamus; pe, pallidum, external segment; pf, parafascicular nucleus of thalamus; pi, pallidum, internal segment; pn, parabrachial pigmented nucleus; po, pontine nuclei; pu, putamen; pv, paraventricular nucleus of the hypothalamus; re, reticular nucleus of the thalamus; ru, red nucleus; ro, nucleus raphes obscurus; sb, subiculum; sc, superior cerebellar peduncle; sn, substantia nigra; so, supraoptic nucleus; sp, subparafascicular nucleus; st, solitary tract; tl, lateral tuberal nucleus of the hypothalamus; tm, tuberomamillary nucleus of the hypothalamus; tr, transentorhinal region (mesocortex); vm, ventromedial nucleus of the hypothalamus; zi, zona incerta.
- Figure 3 Distribution of Lewy bodies in Parkinson’s disease. Diagrammatic representation of pathological data from longitudinally studied cases showing the severity of midbrain dopamine cell loss and Lewy body infiltration over time in an average individual who develops symptoms around 55 years of age versus one who develops symptoms after the age of 70. The severity of dopamine cell loss is related to the duration of symptoms, with those with longer durations having greater cell loss (represented as progressively darker color). The infiltration of Lewy bodies appears more marked in late-onset disease, and in many instances, individuals with late-onset disease have additional agerelated pathologies (represented as cortical plaques). Dementia, as indicated in the lower bar, occurs earlier in the disease in olderonset individuals, consistent with the greater pathology observed.