Neurodegene rative diseases are a heterogeneous group of disorders characterized by gradually progressive, selective loss of anatomically or physiologically related neuronal systems. Prototypical examples include Alzheimer’ s dise ase (AD), Parkinson ’ s diseas e (PD), amyotro phic lateral sclerosis (ALS) and Huntington’s disease (HD). Despite this heterogene- ity , we argue that mitochondrial involvement is likely to be an important common theme in these diseases. Mitochondria are key reguators of ce surviva and death (Fig. 1; for a review s ee ref. 1), have a centra roe in ageing, and have recenty been found to interact with many of the specific proteins implicated in genetic forms of neuro degenerative diseases (Table 1). Mitochondria and ageing By far the greatest risk factor for neurodegenerative diseases such as AD, PD and ALS is ageing, and mitochondria have been thought to contribute to ageing through the accumuation of mitochondria DNA (mtDNA) mutations and net production of reactive oxygen species (ROS). Athough most mitochondria proteins are encoded by the nucear genome, mitochondria contain many copies of th eir own DNA. Human mtDNA is a circuar moecue of 16,569 base pairs that encodes 13 polypeptide components of the respiratory chain, as well as the rRNAs and tRNAs necessary to support i ntramitochondria protein synthesis Mitochondrial dysfunction and o xidative stress in neurodegenerative diseases Michael T. Lin 1 & M. Flint Beal 1 Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. Mitochondria are critic al regulators of cell death, a key feature of neurodegeneration. Mutations in mitochondrial DNA and oxidative stress both contribute to ageing, which is the greatest risk factor for neurodegenerative diseases. In all majo r examples of these diseases there is strong evidence that mitochondrial dysfunction occurs ear ly and acts causally i n disease pathogenesis. Moreover, an impressive number of disease-specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interacti ons of disease-related proteins with mitochondria, hold great promise. 1 Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Room F-610, 525 East 68th Street, New Yor k 10021, USA. using its own genetic code. Inherited mutations in mtDNA are known to cause a variety of diseases, most of which affect the brain and muscles — tissues with high energy requirements. One hypothesis has been that somatic mtDNA mutations acquired during ageing contribute to the physiological decline that occurs with ageing and ageing-related neurodegeneration. It is well established th at mtDNA accumulates mutations with ageing, especially large-scale deletions 2 and point mutations. In the mtDNA con- trol region, point mutations at specific sites can accumulate to high levels in certain tissues: T414G in cultured fibroblasts, A189G and T408A in muscle, and C150T in white blood cells 3 . However , thes e control-region ‘hot spots’ have not been observed in the brain 4 . Point mutations at individual nucleotides seem to occur at low levels in the brain 5 , although the overall level may be high. Using a polymerase chain reaction (PCR)- coning-sequencing strategy, we found that the average eve of point mutations in two protein-co ding regions of brain mtDNA from elderly subjects was ~2 mutations per 10 kb 6 . Noncoding regions, which may be under less selection pressure, potentially accumulate between twice and four times as many 7 . The accumuation of these deetions and p oint mutations with age- ing correates with decine in mitochondria function. For exampe, a negative correlation has been found between brain cytochrome oxidase Table 1 | Proteins that have a function in major neurodegenerative diseases with mitochondrial involvement Disease Genetic causes Function Alzheimer’s disease APP Gives rise to Aβ, the primary component of senile plaques PS1 and PS2 A component of γ-secretase, which cleaves APP to yield Aβ Parkinson’s disease α-Synuclein The primary component of Lewy bodies Parkin A ubiquitin E3 ligase DJ-1 Protects the cell against oxidant-induced cell death PINK1 A kinase localized to mitochondria. Function unknown. Seems to protect against cell death LRRK2 A kinase. Function unknown HTRA2 A serine protease in the mitochondrial intermembrane space. Degrades denatured proteins within mitochondria. Degrades inhibitor of apoptosis proteins and promotes apoptosis if released into the cytosol Amyotrophic lateral SOD1 Converts superoxide to hydrogen peroxide. Disease-causing mutations seem to confer a toxic gain of function sclerosis Huntington’s disease Huntingtin Function unknown. Disease-associated mutations produce expanded polyglutamine repeats 787 INSIGHT REVIEW NATURE|Vol 443|19 October 2006|doi:10.1038/nature05292 Nature PublishingGroup ©2006
