For instance, the number of cases of Alzheimer’s disease (AD) and other dementias, including Lewy body disease and frontotemporal dementia, was estimated by the World Health Organization in 2005 at almost 25 million individuals worldwide, with ∼5 million new cases annually, and is projected SCH727965 to more than double by 2025. Existing approved medicines provide only symptomatic relief, and their chronic use is often associated

with deleterious side effects; none appear to modify the natural course of the diseases. Clearly, the development of effective therapies is hindered by our limited knowledge of the molecular mechanisms underlying these conditions. Despite the phenotypic diversity of neurodegenerative disorders, insights gained in the last decade into small molecule library screening their pathophysiology, especially through genetics, have begun to reveal some underlying themes. These include disturbances in cellular quality control mechanisms (e.g., endoplasmic reticulum [ER] stress, defects in proteasomal and autophagic function, and accumulation and/or aggregation of misfolded proteins), oxidative stress, neuroinflammation, and impaired subcellular

trafficking. Another pathogenic theme that has come to prominence, and which is the focus of this review, is the role of impaired mitochondrial function, not only as it pertains to defects in mitochondrial energy production, but also to mitochondrial dynamics (i.e., organellar shape, size, distribution, movement, and anchorage), communication with other organelles, and turnover. Of necessity, we have substrate level phosphorylation limited our discussion to a subset of neurodegenerative disorders (Table 1), focusing on those that best illustrate our central points. We recognize that this selection introduces a bias, yet the diseases we have chosen encompass the vast majority of patients afflicted with neurodegenerative disease, and thus should

provide a faithful picture of the state of affairs regarding the role of mitochondria in neurodegeneration. Many of the prominent adult-onset neurodegenerative disorders, such as AD, Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), are primarily sporadic, i.e., they occur in the absence of any genetic linkage. However, in rare instances they can be inherited. The phenotypes of both the sporadic and familial forms of these diseases are essentially indistinguishable, implying that they might share common underlying mechanisms. We believe that this similarity justifies the analysis of rare genetic forms of a common sporadic disorder, as it could well illuminate the pathogenesis of both. Moreover, the familial counterparts of all of the common sporadic neurodegenerative disorders are due to mutations not just in a single gene, but in multiple distinct and often ostensibly dissimilar genes.