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Cellular and Molecular Mechanisms of Parkinson’s Disease: Neurotoxins, Causative Genes, and Inflammatory Cytokines

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SUMMARY

1. Parkinson’s disease (PD) is considered to be an aging-related neurodegeneration of catecholamine (CA) systems [typically A9 dopamine (DA) neurons in the substantia nigra and A6 noradrenaline (NA) neurons in the locus coeruleus]. The main symptom is movement disorder caused by a DA deficiency at the nerve terminals of fibers that project from the substantia nigra to the striatum. Most PD is sporadic (sPD) without any hereditary history. sPD is speculated to be caused by some exogenous or endogenous substances that are neurotoxic toward CA neurons, which toxicity leads to mitochondrial dysfunction and subsequent oxidative stress resulting in the programmed cell death (apoptosis or autophagy) of DA neurons.

2. Recent studies on the causative genes of rare familial PD (fPD) cases, such as alpha–synuclein and parkin, suggest that dysfunction of the ubiquitin–proteasome system (UPS) and the resultant accumulation of misfolded proteins and endoplasmic reticulum stress may cause the death of DA neurons.

3. Activated microglia, which accompany an inflammatory process, are present in the nigro-striatum of the PD brain; and they produce protective or toxic substances, such as cytokines, neurotrophins, and reactive oxygen or nitrogen species. These activated microglia may be neuroprotective at first in the initial stage, and later may become neurotoxic owing to toxic change to promote the progression toward the death of CA neurons.

4. All of these accumulating evidences on sPD and fPD points to a hypothesis that multiple primary causes of PD may be ultimately linked to a final common signal-transduction pathway leading to programmed cell death, i.e., apoptosis or autophagy, of the CA neurons.

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ACKNOWLEDGMENTS

Toshi Nagatsu dedicates this paper to the late Dr. Julie Axelrod with great admiration for him for his outstanding scientific achievements as Nobel Laureate and for his extremely warm personality and humanitarian efforts. This work was supported by grants-in-aid for scientific research from the Ministry of Labor and Welfare of Japan (MS), from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MS), and from the Japan Health Sciences Foundation (MS). We are thankful to all of our collaborators, especially Drs. K. Imamura, K. Ono, H. Suzuki, Y. Hashizume, and M. Mogi and to Drs. P. Riederer, Y. Mizuno, T. Kondo, and S. Kuno for their collaboration in supplying us post mortem brain samples from their brain banks.

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  1. Department of Brain Life Science, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Aichi, 464-8601, Japan

    Toshi Nagatsu & Makoto Sawada

  2. Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Aichi, 470-1192, Japan

    Toshi Nagatsu

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  1. Toshi Nagatsu
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Correspondence to Toshi Nagatsu.

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Nagatsu, T., Sawada, M. Cellular and Molecular Mechanisms of Parkinson’s Disease: Neurotoxins, Causative Genes, and Inflammatory Cytokines. Cell Mol Neurobiol 26, 779–800 (2006). https://doi.org/10.1007/s10571-006-9061-9

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