The majority of human neurodegenerative diseases initially involve a discrete set of selectively vulnerable neurons. Identification of the genetic mutations responsible for familial forms of a variety of neurodegenerative disorders—such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), or Alzheimer’s disease (AD)—has provided keen insights into molecular mechanisms of neuronal injury. However, identifying the toxic gain www.selleckchem.com/products/XL184.html or loss of function imparted by disease-causing mutations often fails to explain disease phenotypes, because expression of the mutant protein is

seldom restricted to the affected neuronal populations. Indeed, when the causal mutant gene product of several inherited neurodegenerative diseases is selectively expressed in the vulnerable neuron populations, some mouse models do not yield the complete disease phenotype (Boillée et al., 2006, Brown et al., 2008, Gu et al., 2007 and Yvert et al., 2000). Conversely, widespread expression of disease genes in multiple CNS cell types can recapitulate disease patterns akin to the human disease being modeled, sometimes even when the disease Selleck ABT-263 gene is not expressed in the selectively vulnerable population (Garden et al., 2002). Thus selective neuronal vulnerability in neurodegenerative

disease likely arises from the complex interactions between interconnected cell types. When the net effect of dysfunction in one CNS cell type is the degeneration of a second neighboring or interconnected cell type, the process is known as “non-cell-autonomous” neurodegeneration. There is strong evidence for non-cell-autonomous neurodegeneration in a number of neurological diseases. For example, human transplantation studies in Parkinson’s disease patients have shown that cellular and molecular pathology will develop

in healthy neurons grafted into the brains of affected patients (Dawson, 2008). This finding suggests that replacement of selectively vulnerable neuronal populations may not be sufficient to alleviate disease. Several experimental models of inherited neurodegenerative disease provide direct evidence for non-cell-autonomous degeneration. These include examples of neurodegeneration induced in one cell type, when the disease gene is restricted Lepirudin to a surrounding or connecting cell, or when selective removal of a disease-causing gene from one cell population prevents toxicity in a second cell population despite continued expression of the mutant protein (Clement et al., 2003 and Gu et al., 2005). That selective expression of mutant proteins in surrounding nonneuronal cells (e.g., glia) can induce neurodegeneration has also provided strong experimental evidence supporting the hypothesis of non-cell-autonomous pathogenesis (Custer et al., 2006 and Lioy et al., 2011).