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mtDNA mutations and common neurodegenerative disorders

2005; Elsevier BV; Volume: 21; Issue: 11 Linguagem: Inglês

10.1016/j.tig.2005.08.012

1362-4555

Neil Howell, Joanna L. Elson, Patrick F. Chinnery, Douglass M. Turnbull,

Genetic Neurodegenerative Diseases

The incidence and prevalence of Alzheimer's disease (AD) and Parkinson's disease (PD) are increasing as the population ages. Both disorders have been associated with oxidative stress and mitochondrial dysfunction, and it has been proposed that mutations in the mitochondrial genome have a key role in neurodegeneration in AD and PD patients. Two recent publications propose that heteroplasmic mtDNA mutations are involved in AD and PD. However, when these new studies are considered in relation to the sum of previous evidence, the role of mtDNA mutations in the development of either AD or PD still remains to be established. The incidence and prevalence of Alzheimer's disease (AD) and Parkinson's disease (PD) are increasing as the population ages. Both disorders have been associated with oxidative stress and mitochondrial dysfunction, and it has been proposed that mutations in the mitochondrial genome have a key role in neurodegeneration in AD and PD patients. Two recent publications propose that heteroplasmic mtDNA mutations are involved in AD and PD. However, when these new studies are considered in relation to the sum of previous evidence, the role of mtDNA mutations in the development of either AD or PD still remains to be established. are formed by the fusion of a cell without a nucleus to a cell without mtDNA. Because mtDNA is the only known non-nuclear genetic system in mammals, any trait that is transferred to the progeny cybrids from the parental cells lacking a nucleus is, ipso facto, encoded within the mtDNA. For example, Trimmer et al. [12] have reported that cybrids formed by the fusion of platelets from PD patients (but not from controls) to neuroblastoma cells develop inclusions that have the antigenic and structural properties of Lewy bodies (Table 1), a pathological marker of PD [11]. In a similar fashion, cybrid cell lines formed from AD patient platelets and neuroblastoma cells, relative to those formed with platelets from age-matched controls, showed increased amyloid deposition and oxidative stress [13]. is based on the rationale that, if a major etiological component in AD or PD is a mutation in the maternally-transmitted mitochondrial genome, then the clinical disorder should show a corresponding maternal transmission in a substantial proportion of pedigrees. involve identification of candidate pathogenic mutations by comparing mtDNA sequences from patient groups with those from a control group. Mutations that occur exclusively, or at a significantly higher frequency, in patients are potential risk factors in the disease. refer to sets of mtDNA sequences that are 'related' in the sense of sharing one or more defining sequence changes. The three major ethnic groups (Africans, Asians and Native Americans, and Europeans) are associated with different haplogroups. For example, there are nine major mtDNA haplogroups in populations of European descent. Furthermore, each major haplogroup contains a number of sub-haplogroups that can also be used for studies of population genetics and evolution. For example, European haplogroup H – which is the most prevalent – comprises at least 15 sub-haplogroups [8]. In haplogroup-association studies, disease and control mtDNA sequence sets are assigned to their haplogroups and the frequencies are then compared. A significant difference is interpreted to indicate that mtDNA 'background' has an effect on expression or penetrance of the clinical abnormalities. generally refer to those sequence changes that occur in all of the tissues within the body, including the germline, and that are transmitted from one generation to the next within the limitations imposed by the maternal inheritance. Germline mutations can arise in males, even though they will not be transmitted. refer to those mtDNA sequences changes that arise in a non-germline tissue. Although such mutations cannot be inherited, they can be pathogenic if they reach a sufficiently high level. because there can be thousands of mtDNA molecules in a cell, a mutation might be present in only a fraction of the total population of mtDNAs, a situation termed 'heteroplasmy'. By contrast, if a cell, tissue, organ, or individual contains effectively only a single mtDNA genotype, this is termed 'homoplasmy'. It should be kept in mind that homoplasmy is limited by the resolution of the analysis. For example, individuals are said to be homoplasmic for a particular mtDNA mutation when, more precisely, it is meant that heteroplasmy at this site was not detected within the limits of sensitivity of the assay. neuronal intracytoplasmic deposits of aggregated proteins, which include α-synuclein and ubiquitin. the underlying cause of dementia involves several different pathological processes but the two most common in a hospital population are Alzheimers disease and dementia with Lewy bodies, (a dementia with similar pathological changes to Parkinson's disease).