**9. Membrane trafficking and dynamics in presence of heavy metal ions**

In a study of 12 patients (9 men and 3 women) with Parkinson's disease (Johansson et.al. 2013) erythrocytes showed significant increased concentration of Pb and Ag. The concentration of Cd (9/12) was also higher than that of controls. The observed increased of concentrations of Pb, Ag and Cd may have effects at different levels, e.g. 1. ATP-metabolism and heavy metal ion metabolism 2. Pb, Ag, Cd interactions with dopamine metabolism 3. Axonal transport and membrane trafficking 4. ROS formation by increased activity of hemeoxidases and displaced iron 5. Preapoptosis signals and possible activation of second messengers 6. Pb and porphyrine synthesis

are important for cleaning up residues of senescent erythrocytes. Low concentrations of Cd may be involved in cleaning up heme residues, too high concentration of Cd may support formation of reactive oxygen species (ROS), superoxide anion, hydroxy free radicals, and singlet oxygen. In the porphyrine synthesis it is important that introduction of iron (ferroche‐ latase, frataxin) is not blocked by excess Cd, Pb, Ag (Johansson et.al. 2007). Uncontrolled iron

Possible Relation Between Trace Element Status and Clinical Outcomes in Parkinson Syndrome

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Cd may enter Ca channels (e.g. Gardos channels) in the erythrocyte membrane and introduce interactions in cells (Verbost et.al.1989). Cd, Pb, Ag may release Ca from calmodulin (super‐ family of Ca-carriers) due to weaker binding. Ca Is an important secondary messengers in cells activating e.g. flippases. Liberated Ca may activate translocators, flippases, within the cell (Devaux et.al. 2006). Phosphatidylserine in the inner leaflet may be transferred by trans locators to outer membrane giving an apoptosis marker for the macrophages. Phosphatidyl‐ serine is normally situated below leflet (Martin et.al. 1995). Increased Pb, Cd, Ag may start too

Pb is not known to be essential to man. Pb has redox capacity (Pb2+or Pb4+) and usually associated in reduced form to other molecules. As about 99% of Pb is associated to erythrocytes in blood one target will be the metabolism of erythrocytes. Pb is known to interfere with aminolevulinic acid dehydratase in the heme synthesis (Flindt et.al. 1976, Kelada et.al.2001). Pb is also known to interact with Ca channels by allowing increased input of calcium starting

In the study of 12 Parkinson patients (Johansson et.al.2013) there was no information of food habits for individual patients. In Finland cadmium uptake from food is about 5-10 µg/day, lead 20-66 µg /day, silver was not mentioned. In Sweden cadmium uptake from wheat, rice, potatoes, root-crops is about 10-20 µg /day, lead 15-30 µg /day, silver was not reported. In view of contribution from nutrition of heavy metal ions it is interesting to note that cadmium rich diet in Nigeria decreased Hb and erythrocyte counts in mice (Asagba & Eriyamremu 2007). It cannot be excluded that cadmium, lead in food after long time may accumulate in human erythrocytes and likely decrease erythrocyte counts and hemoglobin synthesis. Smoker may have higher cadmium values in blood but there was no information about smoking habits. Implanters may be a source of metal ion supply. Amalgam is an alloy which is not stable but will release mercury, silver (Johansson E1991, Johansson E et.al.1994, Johansson E and Liljefors T, 1991). Studies indicate that released mercury from amalgam will be found in liver, kidney and brain only minor amounts of mercury will be found in the blood indicating need for looking after other indicators. The effects of silver are often missing but should be included due to effects of silver on important antioxidant compounds containing selenium, sulphur. Some amalgam fillings may have small sticks of guttapercha in the cavity. Some trademarks

may react with oxygen and produce free radicals, Haber-Weiss reactions.

**10.5. Preapoptosis signals and possible activation of second messengers**

early apoptosis of important cells e.g. neurons (Sopjani et.al.2009).

**10.6. Pb and porphyrine synthesis**

too early senescence (Lang et.al. 2010).

**10.7. Possible sources of metal ion supply**
