LES LIAISONS DANGEREUSES: CANCER-RELATED GENES AND NEURODEGENERATIVE DISEASES

摘要

Two of the most clinically problematic classes of disease impacting the world's aging populations are cancer and neurodegenerative disorders. Although there are significant differences between cancer cells and neurons, with the former dividing rapidly and the latter relatively quiescent and non-replicating, a growing body of evidence supports common genetic mechanisms involved in dysregulated cancer cell growth and the progression of neurodegenerative disease (Bennett and Leurgans, 2010). Mutations in a variety of genes involved in regulation of the cell cycle, DNA repair pathways,protein turnover, oxidative stress, and autophagy have been implicated in both of these otherwise dichotomous diseases (Morris et al. 2010). Alterations in a number of genes lead to either carcinogenesis or neurodegeneration, depending on cellular context. Pathways that have emerged as having critical roles in both cancer and neurodegenerative disease include those involving genes such as PARK2, ATM, PTEN, PTPRD,and mTOR. Although neurons are generally considered to be post-mitotic cells that have terminally differentiated and are non-replicating, specific components of the cell cycle machinery may be reactivated in some neurons in response to certain stimuli, such as growth factors (Park et al. 1998), excitotoxicity (Giardina and Beart, 2002; Verdaguer et al. 2002) and DNA damage (Kruman et al. 2004). However, reactivation of the cell cycle in neurons generally progress to apoptosis. Neurons are not mitotically competent, because of the absence of requisite proteins such as certain cyclin-dependent kinases (CDK) and an inadequate subcellular structure for cell division (Nouspikel and Hanawalt, 2003; Ackman et al. 2007), and activation of the core cell cycle machinery in these cells often results in an abortive cell cycle and cell death. Moreover, neurons are unable to use synthesis-related mechanisms of DNA repair such as mismatch repair or nucleotide excision repair, thereby rendering these cells more sensitive to DNA damage, which can trigger apoptosis (Staropoli, 2008). Although the eventual outcome of cell cycle activation or DNA damage in neurons may be apoptosis, normally cycling cells may instead respond with proliferation and possibly tumorigenesis. Ultimately, these dichotomous pathways may manifest as either cancer or neurodegenerative disorders, depending on the cell affected. Disorders such as Parkinson disease (PD), Alzheimer disease (AD), Huntington disease, and ataxia-telangiectasia (AT) provide windows into several genetic determinants of cancer and neurodegenerative diseases. Genes in which dysregulation is capable of producing both outcomes include PARK2, ATM, PTEN, mTOR, APP, and PTPRD. Several pathways involved in cancer and neurodegenerative diseases have been reviewed in the book "Two Faces of Evil: Cancer and Neurodegeneration: Cancer and Neurodegeneration" Edited by Thomas Curran and Yves Christen, Springer (2010).