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

Abstract

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.

Resveratrol Protects Dopamine Neurons Against Lipopolysaccharide-Induced Neurotoxicity through Its Anti-Inflammatory Actions

“…Intensive studies have revealed that several molecular and cellular events, including oxidative stress, mitochondrial dysfunction, proapoptotic mechanisms, and abnormal protein handling, might be involved in the pathogenesis of PD (Nagatsu and Sawada, 2006). However, the mechanisms underlying the neuronal loss in PD are not fully understood.…”

Inhibition of IκB Kinase-β Protects Dopamine Neurons Against Lipopolysaccharide-Induced Neurotoxicity

“…The cardinal clinical symptoms of PD include dyskinesia, resting tremor, rigidity, and gait disturbance. Current therapeutic interventions are limited to alleviating the symptoms of PD, and they fail to halt the progression of neurodegeneration (Gao et al, 2003a).Although oxidative stress, mitochondrial dysfunction, excitotoxicity, and apoptotic processes have been identified as being involved in neuronal degeneration (Nagatsu and Sawada, 2006), the mechanisms responsible for the progressive feature of neurodegeneration are not fully understood. In recent years, increasing evidence has strongly suggested that neuroinflammation is an important contributor to the pathogenesis of neurodegenerative diseases, such as PD, Alzheimer's disease, and multiple sclerosis.…”

“…Although oxidative stress, mitochondrial dysfunction, excitotoxicity, and apoptotic processes have been identified as being involved in neuronal degeneration (Nagatsu and Sawada, 2006), the mechanisms responsible for the progressive feature of neurodegeneration are not fully understood. In recent years, increasing evidence has strongly suggested that neuroinflammation is an important contributor to the pathogenesis of neurodegenerative diseases, such as PD, Alzheimer's disease, and multiple sclerosis.…”

Inflammatory Responses and Regulation in Parkinson’s Disease

“…Inflammation associated with PD can be initiated in the brain by internal factors such as a brain injury, a genetic mutation or some other brain insult or dysfunction (Nagatsu and Sawada 2006;Tansey, McCoy et al 2007;Hirsch and Hunot 2009;Qian, Flood et al 2010) (Figure 1). These sorts of intracerebral inflammatory stimuli activate the microglia which then up-regulate production of inflammatory factors including inflammatory cytokines such as TNFα, IL-1β or IL-6, as well as NO and ROS Nagatsu and Sawada 2006;Tansey, McCoy et al 2007).…”

“…Expression of the inflammatory markers MHC II, TNFα and cyclooxygenase (COX-2) is also higher in SN tissue of patients with PD than in comparable tissue from unaffected controls (McGeer, Itagaki et al 1988;Boka, Anglade et al 1994;Knott, Stern et al 2000). Additionally, levels of proinflammatory mediators, including TNFα, IL-1β, IL-6, (ROS), and eicosanoids, are all elevated in the SN, striatum, cerebrospinal fluid (CSF) and/or peripheral blood mononuclear cells (PBMC) of PD patients (McGeer, Itagaki et al 1988;Qureshi, Baig et al 1995;Mogi, Harada et al 1996;Imamura, Hishikawa et al 2003;Teismann and Schulz 2004;Nagatsu and Sawada 2006;Sawada, Imamura et al 2006;Hirsch and Hunot 2009;Pisani, Moschella et al 2010). Nitric oxide (NO) free radicals are also elevated in PD as indicated by increased nitrite (an indicator for NO) present in the CSF, as well as increased expression of inducible nitric oxide synthase (iNOS) within the SN of PD patients (Qureshi, Baig et al 1995).…”