Mitochondria

All About Parkinson's Disease

Parkinson Diseases Guide By Lianna Marie

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Fig. 5. The scheme how iron increases oxidative stress in mitochondria. Iron released from NM generates superoxide (O2-), which is catalized by SOD. O2- also reacts with nitric oxide (NO) by near-diffusion limit to produce peroxinitrite (ONOO-). ONOO- is a strong radical itself and is decomposed into hydroxyl radical

ONOO"

H2DCF-reactive radicals

Fig. 5. The scheme how iron increases oxidative stress in mitochondria. Iron released from NM generates superoxide (O2-), which is catalized by SOD. O2- also reacts with nitric oxide (NO) by near-diffusion limit to produce peroxinitrite (ONOO-). ONOO- is a strong radical itself and is decomposed into hydroxyl radical

(OH") also reaction (Fig. 5). In the dopaminergic neurons, almost all the iron exists as bound with ferritin or NM, suggesting that NM may be neuroprotective, by chelating iron and other trace metals (Zecca et al., 2001b). Iron content in the substantia nigra increases by ageing but remained stable after the fourth decade of age, but NM content increases further according to ageing (Zecca et al., 2001a). In the postmortem PD brain, increased iron content was detected (Riederer et al., 1989) and recent results using transcranial ultrasonogra-phy revealed that in the substantia nigra of parkinsonian patients, not only the iron content increased, but that of NM decreased (Zecca et al., 2005). These results indicate that in the dopaminergic neurons in PD, the binding capacity of NM with iron was decreased and as a result, cytosolic free iron increased to inhibit ubiquitin-26S proteasome system, as shown in this paper (Gerlach et al., 2003).

Recent proteomics studies indicate the involvement of endosome-lysosome system as a source of proteinacious components in human NM (Tribl et al., 2005). This means NM production is not only ''passive'' accumulation of oxidative products, but some enzymatic system is required for the formation of high molecular aggregates. It requires further studies to elucidate whether the characteristics of NM itself or its synthetic pathway are changed in PD. The future studies on the intracellular mechanisms underlying the selective cell death by iron released from NM may bring out new strategies to prevent or rescue the decline in nigral dopamine neurons in PD.

Degradation

Protein ^

Conformational change

Degradation

Protein ^

Conformational change

Ubiquitin-proteasome system

Cell recovery

Cell death

Inclusion bodies

Fig. 6. The possible mechanism of dopaminergic neuronal death in Parkinson's disease. Iron released from NM increases oxidative stress in the mitochondria, and inhibit 26S proteasome system in the cells. Impairment of 26S proteasome increases accumulation of abnormal proteins to induce cell death

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