Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, affecting 1–1.5% of the total population. While progress has been made in understanding the neurodegenerative mechanisms that lead to cell death in late stages of PD, mechanisms for early, causal pathogenic events are still elusive. Recent developments in PD genetics increasingly point at endolysosomal (E‐L) system dysfunction as the early pathomechanism and key pathway affected in PD. Clathrin‐mediated synaptic endocytosis, an integral part of the neuronal E‐L system, is probably the main early target as evident in auxilin, RME‐8, and synaptojanin‐1 mutations that cause PD. Autophagy, another important pathway in the E‐L system, is crucial in maintaining proteostasis and a healthy mitochondrial pool, especially in neurons considering their inability to divide and requirement to function an entire life‐time. PINK1 and Parkin mutations severely perturb autophagy of dysfunctional mitochondria (mitophagy), both in the cell body and synaptic terminals of dopaminergic neurons, leading to PD. Endolysosomal sorting and trafficking is also crucial, which is complex in multi‐compartmentalized neurons. VPS35 and VPS13C mutations noted in PD target these mechanisms. Mutations in GBA comprise the most common risk factor for PD and initiate pathology by compromising lysosomal function. This is also the case for ATP13A2 mutations. Interestingly, α‐synuclein and LRRK2, key proteins involved in PD, function in different steps of the E‐L pathway and target their components to induce disease pathogenesis. In this review, we discuss these E‐L system genes that are linked to PD and how their dysfunction results in PD pathogenesis. This article is part of the Special Issue “Synuclein”.
One of the mechanisms of the antitumor activity of green tea (2)-epigallocatechin-3-gallate (EGCG) is associated with its effect on epidermal growth factor receptor (EGFR)-mediated signaling transduction pathways. We investigated whether combining EGCG with the EGFR-tyrosine kinase inhibitor (EGFR-TKI) erlotinib may augment erlotinib-induced cell growth inhibition of squamous cell carcinoma of the head and neck (SCCHN) in a mouse xenograft model. In vitro studies with 5 head and neck cancer cell lines revealed that synergistic cell growth inhibition by the combination of EGCG and erlotinib was associated with significantly greater inhibition of pEGFR and pAKT, increased activation of caspases 9, 3 and PARP compared to the inhibition induced by EGCG or erlotinib alone. Erlotinib inhibited phosphorylation of EGFR, stabilizing EGFR at the plasma membrane, whereas EGCG induced EGFR internalization and ubiquitin-degradation, ultimately undermining EGFR signaling. The efficacy of the combination treatment was investigated with nude mice (n 5 25) orally gavaged with vehicle control, EGCG, erlotinib or the combination at the same doses for 7 days, followed by subcutaneous injection with Tu212 cells. Animals were continuously administered the agents 5 days weekly for 7 weeks. The combined treatment resulted in significantly greater inhibition of tumor growth and delayed tumor progression as a result of increased apoptosis, decreased cell proliferation and reduced pEGFR and pAKT compared to the single agent treatment groups. Our results suggest a synergistic antitumor effect of a combined treatment with EGCG and erlotinib, and provide a promising regimen for future chemoprevention and treatment of SCCHN. ' 2008 Wiley-Liss, Inc.Key words: squamous cell carcinoma of the head and neck; (2)-epigallocatechin-3-gallate; erlotinib Squamous cell carcinoma of the head and neck (SCCHN) accounts for 3% of all cancers in the United States, with approximately 45,660 new cases and more than 11,210 expected deaths in 2007. 1 Despite advances in conventional therapies, including surgery, radiation and chemotherapy, the overall survival rate for SCCHN has not significantly improved in the past 3 decades. 2 Overexpression of epidermal growth factor receptor (EGFR) and its ligands TGF-a or EGF has been observed in 80-90% of SCCHN specimens 3-6 and correlates with poor disease-free and overall survival, and increased risk of disease recurrence and metastasis. 6,7 Erlotinib (OSI-774 or Tarceva), an EGFR tyrosine kinase inhibitor (TKI), has shown strong antitumor and chemopreventive efficacies in a variety of cancer types including SCCHN through blocking EGFR-related signal transduction pathways. 5,[8][9][10] Our previous studies showed that EGFR-TKI could inhibit tumor growth through blocking EGFR-related pathways. 3,11 However, the efficacy of monotherapy is severely limited by heterogeneity of the tumor cell population and redundant growth and survival pathways.The development of preventive approaches using specific natural or synthetic che...
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