Summary of ICMS Seminar Club presentation on Friday, November 26, 2021

Published by Dijkstra on

This figure was used as advertisement for the seminar club event. The portrait photograph was kindly provided by Prof. Zecca. The basal ganglia drawing is by Pancrat, the neuron photomicrograph is by Tulemo, and the model figure is from Zucca et al. 2017.

Summary of ICMS Seminar Club presentation on Friday, November 26, 2021.

Title: Neuromelanins in brain aging and neurodegeneration

Speaker: Prof. Luigi Zecca, MD, Senior Researcher at the Institute of Biomedical Technologies-CNR, Milano, Italy

On Friday, November 26, by Zoom, Prof. Zecca gave a presentation to the ICMS Seminar Club of Fujita Health University. He presented a review on neuromelanin research and his groundbreaking discoveries in this field. The presentation, which we recorded, was of excellent didactic quality and is probably understandable from the level of graduate students.

For members of Fujita Health University, the recording is accessible at the “manabi” site :

ふじた学ばこ > 全体 > 研究支援 > 総合医科学研究所 >第3回 ICMS(総医研)セミナー・クラブ（59分）

Unfortunately, we cannot open the recording for a wider audience.

I enjoyed the presentation very much, as did Dr. Tomoyuki Murano, a young neuroscientist working at Fujita Health University, who summarized the presentation as “excellent.” There were 29 participants and, as always, there were many questions during the discussion section. The questions of the audience with answers by Prof. Zecca are shown at the end of this post. Because many aspects of neuromelanins are not fully sure yet, during the actual discussion I found it sometimes hard to grasp the contents, because resembling “questions within a question.” So, I am very grateful that Prof. Zecca took his time to carefully answer the questions again, now in written form, for the readers of this blog post.

The contents of the presentation

Because we recorded the event (see above), and I initially believed that we could make the recoring accessible to a wider audience, my below summary of the contents will only be brief in text. Most figures are screenshots from the recording and include the time indications so that readers (of our University) can easily find the relevant explanations in the recording. The summary does not include all the topics of Prof. Zecca’s presentation.

High concentrations of neuromelanin in the substantia nigra and locus coeruleus

Increasing in the elderly, macroscopically, dark pigments can be observed in the brain regions substantia nigra (SN; Latin for black substance) (Figs. 1 and 2) and locus coeruleus (LC; Latin for blue spot) (Figs. 3 and 4). These pigments are located in neurons that make a lot of neurotransmitter of the catecholamine category, namely dopamine in SN neurons and norepinephrine (also known as noradrenaline) in LC neurons. The pigments consist of neuromelanin structures, which, by the Zecca group, in less abundance and with a slightly different biochemistry have also been found in other brain regions, where they also increase with age (Fig. 5).

Figure 1. Neurons of the substantia nigra innervate the striatum where they can release dopamine. Another region with dopaminergic neurons is the ventral tegmental area, but these neurons have significantly lower amounts of neuromelanin. The drawing is by Slashme.
Figure 2. The number of pigmented neurons in the substantia nigra is much lower in PD patients than in healthy subjects of similar age. The concentration of melanin in the substantia nigra increases with age. The figures are (modified) from Kastner et al. 1992, Hirsh et al. 1988, and Zecca et al. 2002.
Figure 3. Noradrenergic neurons in the locus coeruleus (LC) supply many brain regions with norepinephrine (noradrenaline). The LC is the principal site for the brain synthesis of epinephrine.  SN, substantia nigra; VTA, ventral tegmental area. The drawing is from Bari et al. 2020.
Figure 4. In neurons in the locus coeruleus (LC), the brown pigment of neuromelanin is observed in a granular pattern (as it is in the subtantia nigra). In the LC, the neuromelanin content increases with age (as it does in the subtantia nigra). The middle picture shows the concentration of neuromelanin (ng/mg of wet tissue) in LC of human normal subjects during aging. Values are expressed as mean ± SEM (n = 2). The picture on the right shows the neuromelanin structures in LC neurons as determined by electron microscopy (again, these structures are similar to those in the substantia nigra neurons). These special organelles are membrane-bounded (black arrowhead), contain large amounts of NM pigment (black and electron-dense) which is closely associated with lipid bodies (asterisk) and a protein matrix. In the higher magnification insets, a double membrane delimiting the NM-containing organelle (empty arrowhead) is clearly visible. scale bar=1 μm. The figures and figure legends are from Zecca et al. 2004, and Monzani et al. 2019.
Figure 5. In the brain regions putamen, premotor cortex, and cerebellum, as determined by electron microscopy and biochemistry, melanin-containing pigments consisting of granules 30 nm in size, contained in organelles together with lipid droplets, accumulate in aging. On the left, transmission electron microscopic images of pigmented intraneuronal organelles are shown containing dark pigment (arrow) and lipid droplets (arrowhead). In the middle, scanning electron microscopic images of isolated pigment granules are shown. On the right, the increase of neuromelanin concentrations with aging is shown. The figures are from Zecca et al. 2008.

Degeneration of neuromelanin-containing neurons in Parkinson’s disease

Parkinson’s disease (PD) is mostly restricted to the elderly and concerns the progressive loss of dopamine-producing SN neurons and norepinephrine-producing LC neurons. These are the neuron populations with neuromelanin and therefore the SN and LC in PD patients are not as darkly colored as in healthy controls (Fig. 2; see also Fig. 24). Dopamine and norepinephrine produced by the SN and LC neurons are important for engaging in activities, so that PD patients have difficulties in initiating motor actions and suffer from a tendency for depression. The question is whether, in this story, neuromelanin plays protective or toxic roles, and Professor Zecca obtained evidence for both (see below).

What is neuromelanin?

Neuro stands for neurons and melanin (although there are multiple possible definitions) stands for dark biopolymer pigments of which the synthesis involves the oxidation of tyrosine or dopamine. Melanin production in the skin is a well-organized process, concerning the production of two different types of melanin polymers, named eumelanin and pheomelanin, in specialized organelles (melanosomes) that reside in specialized cells (melanocytes). In contrast, for understandable reasons, neuromelanin has long been considered as “cellular garbage” because of its amorphic shape, inert character, and association in vesicles together with proteins and lipids (Fig. 6). Professor Zecca and co-workers found that neuromelanin contains various metal ions amongst which iron (Figs. 7-to-9), and that—as they inferred from marker distribution—the vesicles are lysosomal in nature with an autophagosomal origin (Figs. 10-to-12). Biochemically, Professor Zecca and co-workers found that neuromelanin consists of eumelanin, pheomelanin, and dopamine-protein adducts, associated with metal ions (Fig. 12; see also the advertisement figure at the top of this blog post). The precise polymer constituents of neuromelanin, and the ratio of the different components of neuromelanin, can differ (e.g., per cell type) and keep being investigated (including by Profs. Shosuke Ito and Kazumasa Wakamatsu of Fujita Health University). Earlier this year, our seminar club had a presentation by Prof. Wakamatsu in which synthesis routes of eumelanin and pheomelanin were already discussed in some detail (see https://futamurayama-science.com/?p=301 for a simple summary). Prof. Zecca provided a convenient overview of how skin melanin is different from neuromelanin (Fig. 13). Prof. Zecca and his group also characterized the lipid contents of neuromelanin, showing the presence of glycerophospholipids and sphingolipids. (Fig. 14).

Figure 6. Neuromelanin-containing organelles in a neuron in the substantia nigra. The figures are from Zucca et al. 2018, and Sulzer et al. 2008.
Figure 7. In substantia nigra neurons with neuromelanin, iron is associated with the neuromelanin and not found in separate iron deposits. The pictures on the left show neuromelanin pigment in substantia nigra dopaminergic as brown granules and reactive ferric iron deposits are blue. The many iron deposits are present in whole substantia nigra parenchyma and principally contained in glial cells (arrows). As shown in the two panels at higher magnification (left bottom), iron deposits are absent in neuromelanin-containing neurons, but non-pigmented neurons show abundant cytoplasmic deposits of reactive ferric iron (arrowhead), consistent with the ability of NM to scavenge iron in stable complexes. In the figures on the right, the top image is shown after using transmission electron microscopy (the arrow indicates neuromelanin; the arrowhead indicates a lipid body) and the bottom image shows the elemental iron distribution obtained by electron spectroscopic imaging. The latter image clearly reveals that large amounts of iron deposits are localized inside the neuromelanin pigment of the organelle (iron element is shown in red color). The figures and figure legends are from Sulzer et al. 2018 and Zecca et al. 2017.
Figure 8. Iron is bound to the melanic component of neuromalin in two different forms. The figures are from Zecca et al. 2004, Zecca et al. 2008, and Zucca et al. 2017.
Figure 9. Besides iron, also other metals are accumulated in neuromelanin. This information can be found in Biesemeier et al. 2016, Zecca et al. 1996, and Zecca et al. 2008.
Figure 10. Summary by Prof. Zecca of the nature of neuromelanin organelles in the substantia nigra.
Figure 11. Nature of neuromelanin organelles in the substantia nigra. The pictures show Western blot analyses for substantia nigra tissue and therefrom isolated organelle fraction, and immuno-electron microscopy for substantia nigra tissue. The proteins specifically detected by antibodies (immunogold is indicated with arrows in the electron micrographs) are: CTSD, Cathepsin D, a lysosomal marker; SNCA, alpha-synuclein, does not particularly associate with neuromelanin organelles; UBC, polyubiquitin-C, a label that may target proteins to proteasomes or lysosomes, is heavily associated with the neuromelanin organelles; MAP1LC3B, microtubule-associated proteins 1A/1B is an autophagic marker that is associated with the neuromelanin organelles.vLipid bodies are indicated by asterisks. The information is from Monzani et al. 2019 and Zucca et al. 2018.
Figure 12. A model postulated by the Zecca group. Possible mechanisms for the synthesis of NM pigment and for the formation of NM-containing organelles. Excess of DA present in the cytosol can be oxidized to DA-oquinone by ferric iron in a catalytic reaction. In the formation of NM pigment, DA-o-quinone can undergo three different pathways: (i) cyclization, further oxidation and polymerization to give eumelanin; (ii) reaction with L-cysteine or glutathione to give cysteinyl-DA compounds then oxidized to pheomelanin; and (iii) conjugation with protein residues to give DA-protein adducts. The latter two reactions seem to be faster and lead to the formation of a protein-pheomelanin core, which is then coated by eumelanin, according to the mixed melanogenesis model. Iron(III) is incorporated into the melanic portion of the forming NM pigment. The resulting undegradable and insoluble pigment is taken into autophagic vacuoles that fuse with lysosomes and other autophagic vacuoles containing lipids, proteins, etc., leading to the formation of NM-containing organelles. These double membrane bounded organelles contain NM pigment along with its components, abundant lipid bodies, and proteinmatrix. This process continues during the entire neuron life and results in the accumulation of NM-containing organelles with aging. The figure and its legend are from Zucca et al. 2018.
Figure 13. Summary by Prof. Zecca of the differences between neuromelanins and skin melanins.
Figure 14. Lipidomic analysis of substantia nigra neuromelanin samples shows the presence of glycerophospholipids and sphingolipids. The data are from Zucca et al. 2018.

Accumulation of catecholamine induces neuromelanin production

For understanding the role of neuromelanin, it should first be known under which conditions neuromelanin is made. Prof. Zecca and co-workers established an elegant system that showed that neuromelanin production was induced by an excess of catecholamines. Namely, they could induce neuromelanin production in rat substantia nigra primary cell culture and PC12 (neuroblastic/eosinophilic) cell line by exposing them to L-DOPA (L-dihydroxyphenylalanine), which is rapidly converted to dopamine in the cytosol (Fig. 15). In accordance, if in such system the excess dopamine is discarded from the cytosol by transgenic overexpression of vesicular monoamine transporter-2 (VMAT2)—which sequesters dopamine into synaptic vesicles—, neuromelanin production is no longer induced (summarized in Fig. 16).

Figure 15. Neuromelanin is induced by L-DOPA in primary cultures of rat subtantia nigra (SN) neurons. The micrographs on the left are bright-field images of living neurons exposed to vehicle or 50 μM L-DOPA (for 11 days). Only in the latter, neural cell bodies (arrows) show dark brown neuromelanin granules that are distributed in a pattern identical to that in SN neurons in human brain. The electron micrographs on the right show neuromelanin granules in a cultured SN neuron exposed to 50 μM L-DOPA (for 14 days). The white arrows in the upper left figure indicate individual NM granules. The granules are essentially identical to those in human SN, although there is little or nolipid bodies. Sections are stained with osmium and uranyl acetate only. Controls do not display NM (not shown). In the electron micrograph at higher magnification (bottom right), a double membrane is discerned (arrows) as in NM granules in vivo. This information is from Sulzer et al. 2000 and Zecca et al. 2008.
Figure 16. Overexpression of VMAT2 in neuronal cultures reduces the production of neuromelanin and the toxic effect of excess catecholamines. Expression levels of VMAT2 in the three tissues ventral tegmental area (VTA), substantia nigra pars reticulata (SNPR), and substantia nigra pars compacta are VTA > SNPR > SNPC as are their neuromelanin concentrations, whereas their vulnerabilities (for loss in PD patients) are in reverse order. This information is from Liang et al. 2004, Sulzer et al. 2000, and Zucca et al. 2004.

The protective role of neuromelanin

Prof. Zecca obtained evidence that neuromelanin has both protective and a toxic roles (summarized in Fig. 17). Neuromelanins are protective by aggregating toxic agents into inert complexes. Among these toxic (when in excess) substances are catecholamines, iron and other metals, which all may contribute to oxidative damage, and a variety of other compounds. Brain iron accumulates in aging, and the increase of neuromelanin helps to remove excess of reactive iron. Prof. Zecca and co-workers found that neuromelanin, or its melanin component as represented by synthetic melanin generated from dopamine, has an anti-oxidative effect, as shown by these agents reducing the production of hydroxyl radicals if added to a Fenton’s reaction sample containing iron, hydrogen peroxide, and salicylic acid (Fig. 18).

Figure 17. A summary by Prof. Zecca about the protective and toxic roles of neuromelanin. The information is derived from Sulzer et al. 2000, Zecca et al. 2003, Block et al. 2007, Zecca et al. 2008, Zhang et al. 2011, and Zucca et al. 2014.
Figure 18. Decrease of hydroxyl radicals production generated by Fenton’s system induced by adding increasing amounts of neuromelanin. Hydroxyl radicals production is given as total normalized concentration of dihydroxybenzoic acids (DHB) determined in samples containing 1 mM salicylate, iron(III)-citrate (0.05 : 0.15 mM), 1 mM ascorbate, 0.5 mM hydrogen peroxide, and varying concentration of either natural neuromelanin (empty symbols) or synthetic dopamine–melanin (DAM) (filled symbols); 100% corresponds to 0.025 mM DHB in the case of DAM and 0.03 mM in the case of neuromelanin. Values are expressed as mean ± SD (n = 3). This figure and legend are from Zecca et al. 2008.

The toxic role of neuromelanin

In the substantia nigra of Parkinson’s disease patients, extracellular neuromelanin of degenerated dopaminergic neurons can be found and activated microglia accumulate around the degenerating/degenerated neurons (Fig. 19, in which Prof. Zecca kindly shows micrographs from work of Prof. Toshiharu Nagatsu of Fujita Health University). Prof. Zecca and co-workers found that isolated neuromelanin activates microglia (brain immune cells) which then migrate towards it and digest it (Fig. 20). Moreover, they found that activation by neuromelanin induces microglia to kill neurons, both in vitro and in vivo (Fig. 21). Prof. Zecca has proposed that the stimulation of microglia through neuromelanin released by dying neurons establishes a vicious cycle of neuroinflammation and neurodegeneration (Fig. 22).

Prof. Zecca and co-workers also found that neuromelanin-containing neurons express MHC class I, and that CD8+ cytotoxic T lymphocytes (CTLs) can be associated with these neurons (Fig. 23). They proposed that the MHC class I restricted recognition by CTLs is one of the mechanisms by which neuromelanin containing neurons are killed in Parkinson’s disease (Fig. 24).

Figure 19. In the substantia nigra of Parkinson’s disease, extracellular neuromelanin of degenerated dopaminergic neurons can be found (arrows in top right micrograph) and activated microglia accumulate around the degenerating/degenerated neurons. The micrographs are from Kaneko et al. 2012 and Imamura et al. 2003.
Figure 20. In vitro, neuromelanin activates microglia which migrate towards it and digest it. If rat or mouse migroglia were incubated with human neuromelanin, they were activated as shown by chemotaxis, changes in morphology, and the production of cytokines an intracellular reactive oxygen secies (iROS). The micrographs at the top show rat microglia before (A) and after 24 h incubation with human neuromelanin (B), where it then can be detected in the perinuclear cell soma (arrows) while the cells changed their morphology to a more amoeboid phenotype. The micrographs at the bottom show a series of differential contrast images of microglial phagocytosis and degradation of a large particle (~ 14 nm diameter) of neuromelanin in ventral midbrain / astrocyte / microglial co-culture at 2 h intervals excerpted from a video http://www.sulzerlab.org/videos/NMmicrogliaDIC.mov. This information is from Wilms et al. 2003 and Zhang et al 2011.
Figure 21. Activated microglia induce neurodegeneration in vitro and in vivo. The micrograph on the top right is of a rat ventral midbrain / astrocyte / microglial co-culture that has been incubated with human neuromelanin for 72 h. The cells were immunolabeled for dopaminergic neurons by TH (green) and activated microglia by OX-42 (red). Examples of NM particles that have been phagocytosed are indicated by the single-headed arrows. The double-headed arrow indicates an example of a swollen neurite varicosity, which is several-fold larger than typical varicosities in these neurons (average ~1.2 μm) which can also be observed. The swollen varicosities are an indicator of toxicity. The pictures at the bottom show the results of immunostaining in the rat substantia nigra 10 days after human neuromelanin injection. Rats received either phosphate buffered saline or NM at 1 μl/min for 4 min, then the total amount of NM injected into the rat SN was 3.4 μg. The needle was left in place an additional 2 min. Arrows indicate the site of injection within the SN. Representative TH immunostaining of the SN in a NM-injected rat, and in a vehicle-injected rat (saline). Representative SN Iba-1stained microglia from a NM-injected rat and from a vehicle-injected rat are also shown. The results are quantified in the histogram on the right. This information is from Zhang et al 2011.
 Figure 22. Summary of the neurotoxic role of neuromelanin through the activation of microglia.
Figure 23. Using double immunolabel for MHC class I and CD8+ (a marker for cytotoxic T lymphocytes, aka CTLs), sometimes close proximity of MHC class I expressing neuromelanin-positive neurons and CD8+ CTLs was observed in postmortem human substantia nigra. The arrow indicates a CD8+ CTL in contact with a NM+ neuron. The micrographs are from Cebrian et al. 2014.



 Figure 23. Discussion of neurodegenerative roles of neuromelanin involving MHC class I. The model has been presented in Cebrian et al. 2014.

Measuring neuromelanin abundance (as a representative of PD progression) by magnetic resonance  imaging (MRI)

Already in 2002, Prof. Zecca and co-workers proposed to use the loss of neuromelanin in Parkinson’s disease (PD) as a diagnostic parameter to be measured by magnetic resonance imaging techniques. This made sense, because neuromelanin includes a high concentration of iron, and because in Parkinson’s disease patients there is a 30-80% decrease of neuromelanin. A few years later, another research group established MRI analysis indeed, and nowadays MRI can be used to estimate the level of neuromelanin and thus of PD disease progression in the substantia nigra and locus coeruleus (Figs. 24-27). This system can be used to confirm diagnosis and evaluate the progression of PD. This method has not been sufficiently fine-tuned yet for pre-symptomatic diagnosis of PD, but Prof. Zecca has good hope that—in the near future—it may.

Figure 24. NMR imaging shows lower concentrations of neuromelanin in the substantia nigra and locus coeruleus of a PD patient compared with a healthy control. These images are from Isaias et al. 2016.
Figure 26. Summary by Prof. Zecca on magnetic resonance imaging (MRI) of neuromelanin. The articles referred to are Trujillo et al. 2017 and Cassidy et al. 2019.
Figure 27. Summary by Prof. Zecca on how magnetic resonance imaging (MRI) of neuromelanin may contribute to early diagnostics of Parkinson’s disease (PD) and differentiation between PD types.

Collaborations

Professor Zecca kindly thanked his collaborators that contributed to the data shown in his presentation, among which Professors Shosuke Ito and Kazumasa Wakamatsu of Fujita Health University (Fig. 28).

Figure 28. Prof. Zecca expressed his gratitude to the collaborators with whom together he has generated the presented data.

Questions by the audience

(These are the questions and answers that I remember. They are modified for clarity)

Question 1.

Neuromelanins in the substantia nigra and locus coeruleus are produced from dopamine and norepinephrine, respectively. These neurotransmitters are related to feelings of excitement (dopamine) and activity/anxiety (norepinephrine), which, at least for the excitement and activity parts, are lower in elderly people. So why then do elderly people have more neuromelanin? Do they produce more dopamine and/or epinephrine, or is it less efficiently secreted? If the latter is true, could excess neuromelanin production be halted if people would keep doing exciting things?

Answer: Neuromelanin is continuously synthesized and accumulated during the life and its turnover is very slow. Then neuronal content of neuromelanine remains high although catecholamine levels decrease in aging.  In psychosis typically present in schizophrenia there is an increased activity of dopamine system. The psychosis are conrolled by drugs, psychological therapies, and social support.

Question 2.

For Parkinson’s disease (PD) you mentioned an inflamed situation with activated mircoglia that contribute to neurotoxicity. How can you be sure that the neurons did not die in a more controlled fashion, namely by apoptosis, with the microglia just playing a role in that apoptosis and/or in clearing the cellular debris?

Answer: Neurons can obviously die by apoptosis, autommune mechanism and others. After neuronal death microglia can work to clean up cellular debris.

Question 3.

Research shows that people with PD have a higher risk of developing melanoma, and people with melanoma have a higher risk of developing PD [e.g., see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130416/pdf/jpd-8-jpd171263.pdf]. Do you think that treatment with L-Dopa [the precursor of dopamine which can transfer the blood-brain barrier and is used as a drug to increase dopamine concentrations], which is a common treatment in PD, can inadvertently promote melanoma?

Answer: As far as I know no one of the drugs to treat PD (L-DOPA, dopamine agonistst and others) is suspected to promote or increase the risk for melanoma.

Question 4.

You mentioned that dopaminergic neurons with neuromelanin express MHC class I molecules that present peptides at the cell surface that stimulate cytotoxic T cells. Which peptides do you think are involved?

Answer: We have shown in cultures that peptides derived from ovalbumin can be presented by MHC-I on neuronal membranes so that neurons are targeted by CD8+ Lymphocytes. These peptides in human brain can be of any type and generated by proteolytic processing of proteins in neurons or other cells, then the peptides are loaded on MHC-I inside neurons and presented on membrane.

Question 5.

Do you think that dopaminergic neurons possess tyrosinase?

Answer: It was demonstrated by our group and others with different methods including LC-MS that dopaminergic neurons do not have tyrosinase

Question 6.

Do you think that melanocytes possess tyrosine hydroxylase?

Answer: Yes indeed tyrosine hydroxylase was reported to be present in human melanosomes

Question 7.

Do other neurons besides catecholaminergic neurons also possess neuromelanin?

Answer: Yes we have shown that neuromelanine occurs also in brain regions without catecholaminergic neurons. In fact phenolic precursors like modified catechols different than dopamine and noradrenaline can be oxidized to generate melanic compounds.

Question 8.

Does neuromelanin accumulation inhibit tyrosine hydroxylase activity?

Answer: I think neuromelanin accumulation does not inhibit tyrosine hydroxylase activity. In fact you can see neurons having high neuromelanin and  that highly express tyrosine hydroxylase.

Question 9.

Why does neuromelanin not degrade like skin melanin [which consists of eumelanin and pheomelanin]?

Answer: Neuromelanin is a complex compound containing melanic, lipid and peptide component. It is insoluble and highly stable in brain tissue and in isolated form. It is very different from skin melanin. Autolysosomal organelles containing neuromelanin are different fom melanosomes and are very stable.

Question 10.

Can the amount of neuromelanin be used as a marker for the progression of PD?

Answer: Yes, we have shown that neuromelanin concentration decreases during PD and this decrease can be imaged by MRI to diagnose PD.

Question 11.

Why does treatment with L-Dopa not increase the amount of neuromelanin?

Answer:There are not conclusive data but in principle it is possible that in PD patients the L-Dopa treatment increases the content of neuromelanine in the spared neurons.

Question 12.

There appears to be a switch from neuromelanins being protective to neuromelanins being toxic. Can you elaborate on the nature of that switch?

Answer: Extraneuronal neuromelanins are always toxic since they activate mcroglia and induce neurodegeneration. Intraneuronally the synthesis of neuromelanins is protective as it removes excess cytosolic catechols non accumulated in synaptic vesicles, which would cause toxicity. However intraneuronally an autoimmune mecahnisn of neurodegeneration may occur through the loading of foreign peptides on MHC-I and presentation on neuronal membranes, then neurons would be attacked by CD8+ cell.

Question 13.

Why is PD negatively associated with the risk of many cancers (with the exception of melanoma) [e.g., see https://www.frontiersin.org/articles/10.3389/fnagi.2020.00060/full]?

Answer: This relationship seemed clear in the past. However it has become more controversial recently with epidemiology studies reporting contradictory results, as many variables are present and some are not controlled. Even the few experimental studies did not show consistent results.

Question 14.

The model seems to say that increased iron concentrations in the brains of the elderly promote neuromelanin formation and thereby induce neuron mortality. Can’t people change these iron concentrations by changing their diet?

Answer: The involvement of iron in neuromelanin synthesis is a phenomenon starting early in life. During aging total iron (mainly built by ferritins) in substantia nigra accumulates. The iron bound to neuromelanin is non toxic.  The reactive/toxic iron is present in hemosiderin and accumulates in aging. The iron metabolism in brain and the accumulation of reactive iron are independent from peripheral and blood iron, then diet does not significantly affect brain iron.

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