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and science will be no exception. This also makes us support would be of great value and would aware of the worldwide context of our neuroscien- undoubtedly help us to reach these objectives tific research. It seems that neuroscience in the during the transitional stages. Republic of Georgia has proved its worth and must now expand to face further demands. We must (1) maintain and develop our research base in neuroscience, despite inevitable political and economic problems in the future, (2) change and improve the ADDENDUM level of teaching neuroscience in the university, and In the article by J. H~mori on Hungarian especially in the medical colleges, by creating an eduction system that is competitive at an interNeuroscience (March 1991, Vol. 14, pp. national level. This will necessitate some means 91-93), there was an omission from the list of sending young, creative people to universities of Szent~gothai's pupils on page 91. It abroad and re-establishing and maintaining a topshould read: 'The pupils of Szent~gothai quality library system. We must also (3) improve the himself include G. Sz~kely, J. H~mori, scientific standard and productivity of research, P. Somogyi and M. R~thelyi (neuroanatomy), perhaps (i) by making a system of open competition and B. Flerko, B. Hal~sz and M. Palkovits for research grants, which would be available for (neuroendocrinolo~y), among others'. young scientists and judged by groups of experts from abroad, (ii) by increasing scientific communication (for example, by visits to international meetings and sharing scientific information), (iii) by training people in established laboratories abroad and In the next issue of TINS, this series continues (iv) by collaborating in research projects. with an article on neuroscience in Yugoslavia All these points emphasize the extremely hard by Ivica Kostovid and Milo~ Juda], and a work, economic improvements, understanding and response to J. H~mori's article on Hungary. support that we need from our newly elected National Parliament in order to achieve these aspirations. International solidarity and practical

Neurologicaldiseaseandmitochondrialgenes A. E. Harding A. £ Hardingis at the Dept of Clinical Neurology, Institute of Neurology, Queen Square, London WC1N3BG, UK.

MitochondHa contain 2-10 copies of a small, double-stranded, circular DNA moleculethat is exclusivelymaternally transmitted. Until recently, the only function of mitochondrial DNA that had any possible signihcancefor clinicians was the fact that the mutation confernng chloramphenicol resistance occurs in one of the mitochondrial ribosomal RNA genes. It is now clear that major deletions and point mutations of mitochondrial DNA causehuman diseases, chiefly mitochondrial myopathies and encephalopathies, and Leber's hereditary optic neuropathy. All mammalian cells contain at least two distinct genetic systems, of which the nuclear genes are numerically, functionally and pathologically most important. Mitochondria have their own genome, each containing 2-10 double-stranded circular DNA molecules, about 16.6 kilobases (kb) in length. The mitochondrial genome contributes about 1% of total cellular DNA. Human mitochondrial DNA (mtDNA) has been entirely sequenced ~. It differs from nuclear DNA slightly in its genetic code and also because it contains very little noncoding sequence (Fig. 1). MtDNA encodes two ribosomal RNAs, 22 transfer RNAs (tRNAs), and 13 of the 67 or so subunits of the mitochondrial respiratory chain and oxidative phosphorylation system: seven sub-

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units of complex I (NADH dehydrogenase, ND); cytochrome b (complex liD; subunits I, II and III of cytochrome oxidase (complex IV); and subunits 6 and 8 of ATP synthetase 1'2. MtDNA has been shown to be transmitted exclusively by females in many species, including humans. MtDNA appears to be identical within and between individuals in a single maternal line. This is in some ways surprising as the mutation rate of mtDNA is high, and extensive mtDNA nucleotide sequence divergence occurs between different maternal lines. Restriction mapping of mtDNA in different human populations can be used to trace their origins 3. During the past three years, defects of the mitochondrial genome have been described in a number of human diseases. These are summarized in Table I.

Clinical and biochemical features of mitochondrial myopathies The term mitochondrial myopathy is applied to a clinically, biochemically and genetically heterogeneous group of diseases that usually show mitochondrial structural abnormalities in skeletal muscle4. Ragged red fibres, containing peripheral and intermyofibrillar accumulations of abnormal

© 1991.ElsevieSci r encePublishersLtd,(UK) 0166 2236/91/$02.00 -

TINS, Vol. 14, No. 4, 1991

perspectives mitochondria and visualized with the modified Gomori trichrome or succinic dehydrogenase stains, are the morphological hallmark of these disorders (Fig. 2). These were initially observed in patients displaying syndromes of progressive external ophthalmoplegia (PEO) and/or muscle weakness, often enhanced by exercise. Morphological mitochondrial abnormalities in muscle have subsequently been described in children and adults with complex multisystem disorders predominantly affecting the CNS. These patients might have psychomotor retardation, dementia, ataxia, seizures, movement disorders, stroke-like episodes, pigmentary retinopathy, deafness and peripheral neuropathy in various combinations. Involvement of the heart, endocrine system, kidney and haemopoietic tissues has also been reported 4's. Some cases of mitochondrial myopathy involve distinctive clinical syndromes. These are (I) the Kearns-Sayre syndrome (KSS), a combination of PEO and pigmentary retinopathy that develops before the age of 20 and is associated with cardiac conduction defects, ataxia and increased cerebrospinal fluid protein concentrations, (2) myoclonus epilepsy with ragged red fibres (MERRF) and (3) mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS)5. There is clinical overlap between these syndromes4 and they are biochemically and genetically heterogeneous. They do represent combinations of some of the more striking features of the mitochondrial myopathies and as such are useful in clinical practice. Most patients with mitochondrial myopathy show a pathological increase in serum lactate concentrations during and after exercise, suggesting a defect of aerobic metabolism in muscle mitochondria. Defects of the mitochondrial respiratory chain are demonstrable in most cases using polarography (studying oxygen uptake in isolated mitochondria with various respiratory chain substrates) or enzymatic assays. These usually involve complexes I (NADH-coenzyme Q reductase), III (ubiquinolcytochrome c reductase) or IV (cytochrome oxidase), alone or in combination 4'5. There is little correlation between these biochemical defects and the clinical features.

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Table I. Geneticdefects in mitochondrialdiseases Disease MtDNA defects Large deletionsof mtDNA

Mitochondrial myopathies(PEO,KSS) Pearson'ssyndrome Duplicationsof mtDNA Mitochondrial myopathies(KSS) Point mutations of mtDNA Mitochondrial myopathies(MERRF,MELAS) LHON RP, ataxia,dementia, neurogenicweakness

Nuclear defects

Probably mitochondrial myopathies Mitochondrial myopathieswith multiple mtDNA deletions

Abbreviations: KSS,Kearns-Sayresyndrome; LHON, Leber'shereditaryoptic neuropathy; MELAS, mitochondrial encephalopathywith lactic acidosis and stroke-like episodes;MERRF,myoclonusepilepsywith raggedred fibres; PEO,progressiveexternal ophthalmoplegia;RP,retinitispigmentosa.

Molecular genetics An association between human disease and defects of the mitochondrial genome was established when it was shown that 9 of 25 patients with mitochondrial myopathy had two populations of mtDNA in muscle, one of which was deleted by up to 7 kb8. (Leukocyte mtDNA was normal.) The proportion of abnormal muscle mtDNA ranged from 20% to 70%. All patients with deletions reported to date have had PEO, and deletions are found in about 90% of cases of KSS. MtDNA deletions have not been observed in patients with proximal myopathy without ophthalmoplegia, or in predominant CNS disease such as MERRF or MELAS, and they are rare in patients who have affected relatives9-11. Tandem duplications of one population of mtDNAs have also been described in blood from two patients with mitochondrial myopathy and diabetes, one with the features of KSS12. These duplicated molecules might be mtDNA dimers with one copy of the molecule partly deleted. About 40% of patients with morphologically defined mitochondrial myopathy have a deleted population of muscle mtDNAs (Fig. 1) ~°'~. None of the deletions studied so far has been proved to include the origins of transcription or replication of either strand of mtDNA: such molecules would not be expected to survive. Approximately one third of Genetic aspects deletions appear to be identical, extending over Approximately 20% of adult patients with 4.9 kb within the region 8470-13460 base pairs mitochondrial myopathy have similarly affected (bp). The deletion junction in these and other cases relativess. No consistent pattern of inheritance has has been sequenced after amplifying the flanking been identified for any of the clinical syndromes or region by the polymerase chain reaction (PCR)13r. respiratory chain defects. Maternal transmission of The 'common deletion' junction is bridged by 13 mitochondrial myopathy to offspring is considerably nucleotides that normally occur as a direct repeat more frequent than paternal transmission, in a ratio within the regions 8470-8482 and 13 447-13 459 of approximately 9 : 1 (Ref. 6); Egger and Wilson 7 bp (Fig. 3). About 50% of mtDNA deletions (in 70% proposed that this was explicable on the basis of of patients) are flanked by perfect direct repeats of mitochondrial inheritance. Support for this hypoth- 5-13 bp ~3. Possible mechanisms for deletion foresis comes from the observation that most patients mation thus include recombination events mediated with mitochondrial myopathy have respiratory chain by enzymes that recognize short homologies, or defects that involve complexes containing subunits slippage occurring during replication. encoded by mtDNA, which, as mentioned above, is It is not clear when mtDNA deletions arise. Only exclusively maternally transmitted. two reported patients with deletions had clinically TINS, VoL 14, No. 4, 1991

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Fig. 1. Linearized map of the mitochondrial genome, also showing (from top to bottom) the extent of deleted regions in 25 patients with mitochondrial myopathy and location of coding regions. The dotted lines at either end of the deletions represent their upper and lower Case 38 limits, defined by the presence or I-- -- - - I I----I absence of restriction sites. The small Case 58 open circles in the map represent I- - I I --I tRNAs. Abbreviations: A, ATPase; Case 24 CO, cytochrome oxidase; cyt b, I ----I s--I cytochrome b; ND, NADHcoenzyme (9 reductase subunits; Case 31 I. . . . I I---I N/C, non-coding region; OH, OL, Case 83 origins of heavy and light strand I----I .I. . . . . I replication; 12S, 165, ribosomal RNAs. (Taken, with permission, from Cases 16, 2 5 & 8 5 --I

Ref. 10.) Case

t--i

28

I

.I--I

Case 70 I--I

I-I

Case 2

I--I

0 i N~C

I 0

IIl

0L

I 2

I 4

I----I

Case 43

I 6

I------I

Cases 1,17,18,19,26,27,30,44,45,48,67,68 I-I H COII A 8 C O I I I N D 3 N D 4 L

I 8

affected relatives ~. Muscle mtDNA deletions were undetectable by Southern blot analysis in the mothers of three patients 9, so it seems probable that in most cases the deletions occur during oogenesis. The survival of deleted mtDNA molecules in muscle is compatible with the observation that the number of muscle fibres does not increase significantly after early fetal life s. This might also apply to the CNS tissue of patients who display predominant CNS disease and mtDNA deletions. A high proportion (72%) of deleted mtDNAs was observed in the brain of one patient with KSS, and 52% of liver mtDNAs were also deleted ~°. Frequent cell division in leukocyte precursors would be expected to select against cells containing genetically defective mitochondria. Only one case of mitochondrial myopathy, with KSS, has been shown by Southern blotting to have a small proportion of deleted mtDNAs in fibroblasts and leukocytes I°. Low numbers of deleted mtDNAs might be detectable in patients' blood after amplification by PCR (a more sensitive technique). Apart from cases of KSS, patients with mitochondrial myopathy and demonstrable mtDNA deletions are relatively mildly affected clinically. This is reflected by biochemical studies of mitochondria, which tend to show a normal or slightly reduced respiratory capacity. In those with respiratory chain defects, there is some correlation between the site of the defect and the deleted mitochondrial genes, although patients with apparently identical deletions can have different biochemical and clinical features I~. There is no obvious correlation between the proportion of abnormal mtDNA in the muscle 134

I 10

I 12

& 69 ND6

I 14

N/C

I 16 kb

sampled and either clinical or biochemical severity. All the deletions reported definitely involved a number of tRNAs. Such deletions would thus be expected to have a detrimental effect on translation of all mitochondrially encoded subunits of the respiratory chain, unless the deleted mtDNAs and normal molecules are physically close enough to share tRNAs within mitochondria. Deleted mtDNAs are transcribed, but the mRNA fusion product that is derived from the deletion junction is probably not translated, suggesting that intergenomic cooperation does not occur, at least in some cases14. The functional effects of deleted mtDNAs must depend not only on their distribution within mitochondria, muscle fibres and different tissues, but also on the absolute amount of normal mtDNA and its distribution. Studies of the distribution of normal and deleted mtDNAs in the muscle of one patient by means of in situ hybridization initially suggested that there was a correlation between the relative proportions of each and segmental loss of oxidative function, as determined by measuring cytochrome oxidase activity in muscle fibres 15. Other authors have reported that deleted mtDNAs were virtually confined to ragged red fibres, which often do not stain for cytochrome oxidase, but that normal mtDNA was uniformly distributed throughout the muscle~6. These observations suggest that loss of oxidative function in some muscle fibres is not due to deficiency of normal mtDNA, but is perhaps related to interference from the predominance of molecules with deletions in these fibres. It was suggested that this could result from an imbalance between the numTINS, VoL 14, No. 4, 1991

perspectives bers of mRNAs and tRNAs (the genes for some of which are included in the deletions) in organelles containing a high proportion of deleted mtDNAs, resulting in stalling of translation at scarce tRNA codons and impaired mitochondrial protein synthesis 16.

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A

Pearson's syndrome MtDNA deletions have also been observed in lymphocytes from patients with Pearson's syndrome, a disorder displaying neonatal pancreatic and hepatic insufficiency, and pancytopoenia 17. Structural abnormalities of leukocyte precursor mitochondria were shown in the original report of this disorder is. A patient with the clinical features of Pearson's syndrome survived, but developed KSS and the histological features of mitochondrial myopathy in later childhood; the 'common' mtDNA deletion was present in both leukocytes and muscle 19. This suggests that Pearson's syndrome and KSS represent different phenotypes of the same molecular defect, the variable combination of symptoms presumably depending on the distribution and amount of deleted mtDNA.

MtDNA point mutations in mitochondrial myopathies Given that the predominance of maternal inheritance provided a major impetus for investigating the mitochondrial genetic hypothesis in mitochondrial myopathy, it is perhaps slightly ironic that the first mtDNA defects identified - large deletions - are not usually inherited. A point mutation of mtDNA is more likely to be transmitted than mtDNAs with large deletions, and this has recently been demonstrated in a large kindred with maternally inherited MERRF2°'21. This was an A to G transition at position 8344 (a conserved nucleotide) in the lysine tRNA gene, which also occurred in two other unrelated patients with MERRF, but in none of 75 control subjects. All the patients had a mixture of mutant and normal mtDNA (heteroplasmy), the latter ranging from 2% to 27%. Disease severity showed some correlation with the proportion of mutant mtDNA when age was taken into account; for a given proportion of normal mtDNA, older subjects were more likely to have manifestations of MERRF than younger ones. The mutation at position 8344 was also demonstrated in five Italian pedigrees with MERRF, but it was absent in two other cases of MERRF and patients with other mitochondrial myopathy phenotypes 22. A heteroplasmic mtDNA point mutation, in the leucine tRNA gene, has recently been described in 26 of 31 patients with MELAS23.

B

Fig. 2. Transversesections of skeletal muscle stained with succinic dehydrogenase from (A) a normal subject and (B) a patient with mitochondrial myopathy. Fibres showin& increased subsarcolemmal enzyme activity (darker stainin&) in the patient represent ra&&ed red fibres. TINS, VoL 14, No. 4, 1991

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perspectives amino acid L strand H strand

on leu

disease pro

pro

. ser

. pro

.

. leu

= ala

ala

stop

C TIA C C T C C C T C A C C A T T G G C A G C A T A G A A C C G T C G T A T C GATGGAGGGAGTGGTI 8470 13447

repeat 1 or repeat 2

8482 bp 13459 bp

Fig. 3. The deletion junction in mutant mtDNA, which is bridged by a 13 bp sequence (boxed region). This occurs as a direct repeat at 8740-8482 and 13 447-13 459 bp in normal mtDNA. The exact breakpoint cannot be determined as it could be at either end of the repeat or within it. The deletion causes a frameshift at position 13 460, and termination of translation occurs three codons downstream.

Other genetic defects in mitochondrial myopathies

about 50% of LHON families have the mutation at position 11 77828'29. This genetic heterogeneity has some clinical correlates; useful recovery of visual function was not observed in families with the mutation at position 11 778, but some improvement had occurred in members of all those without this mutation 28. Studies in the UK showed that the mutation at position 11 778 was heteroplasmic in the majority of subjects studied 28. Individuals with a high proportion (>95%) of mutant mtDNA appeared more likely to develop or transmit the disease. The proportion of mutant mtDNA in the optic nerves or their vasculature might partly determine the likelihood of developing the disease. However, this would not explain the predominance of males with LHON nor why some family members with a high proportion of mutant mtDNA remained unaffected. Linkage between the locus DXS7 on the proximal short arm of the X chromosome and liability to develop visual loss in LHON families has recently Leber's hereditary optic neuropathy been suggested3°; this applied to both those with Leber's hereditary optic neuropathy (LHON) and without the mtDNA mutation at position causes acute or subacute blindness in young adults, 11778. It could be that the latter have another usually males. At onset the optic discs are swollen mtDNA mutation. These observations suggest an with tortuous retinal arterioles and peripapillary interaction between mitochondrial and nuclear telangiectases, but optic atrophy is apparent within genes in determining the LHON phenotype. They two months. The pattern of transmission of LHON provide an explanation for the predominance of suggests mitochondrial inheritance 26. About 85% of males with this disease, since affected females must patients are male, and 18% of female carriers are be homozygous for the X-linked allele for susceptiaffected; 50-100% of the sons of carriers are bility to visual loss, which appears to be common in affected, and 70-100% of daughters of female the general population. What is still not clear is how carriers are carriers. Affected descendants of male a fairly conservative amino acid change in a respirpatients have never been described, making X- atory chain subunit is related to the development of linked inheritance unlikely. subacute blindness in young adult life. EnvironmenA point mutation of leukocyte mtDNA (at position tal factors, such as cigarette smoking, have been 11 778) was reported in 9 of 11 LHON pedigrees in suggested 27. The apparent tissue specificity of the the USA27. This led to an amino acid change from disease is particularly difficult to explain as the arginine to histidine in a subunit of NADH- mitochondrial LHON mutation is present in a high coenzyme Q reductase, and loss of a recognition site proportion of leukocyte mtDNAs. Complex I defor the restriction endonuclease SfaNI. The mutation ficiency has been observed in platelets from memwas found in all affected or unaffected, maternally bers of a large family with LHON, but some afrelated individuals in these families and it appeared fected members had atypical features, including to be homoplasmic, i.e. present in all mtDNA those suggesting a mitochondrial encephalopathy 31. molecules analysed. In the UK and Finland, only The mtDNA mutation at position 11 778 was not It is unlikely that all cases of mitochondrial myopathy are due to defects of the mitochondrial genome, since nuclear genes code for the majority of the respiratory chain subunits, as well as controlling their transport into mitochondria and subsequent assembly into functional enzyme complexes. Transcription and translation of mitochondrial genes are also dependent on the nucleus. Evidence that mitochondrial myopathy might be caused by mutant nuclear genes was provided by the observation that some patients with complex I defects have specific deficiencies of nuclear products 24. Nuclear genetic defects can also cause mtDNA deletions in some instances. A family with autosomal dominant mitochondrial myopathy in which affected individuals had multiple muscle mtDNA deletions of variable length has been described25. It was suggested that this disorder was caused by a nuclear defect involving mtDNA replication.

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perspectives present in this family and sequencing studies did not identify any other candidate mutations in the ND3, ND4 or ND4L genes (Fig. 1), or the contiguous tRNA genes 32.

on disease

analyse mtDNA from the brain tissue of patients dying from Parkinson's disease, no deletions were found, but two new polymorphisms not present in controls were observed; the significance of these has yet to be established 3s. It is possible that any defects of the mitochondrial genome in Parkinson's disease could be secondary to the mutagenic effects of free radicals. Deleted mtDNAs at low abundance have been detected in brain tissue from patients with Parkinson's disease by means of PCR, but this was also the case in elderly normal subjects 39. This is interesting with respect to the suggestion that accumulation of mtDNA mutations might contribute to ageing 4°.

Neurological disease associated with a point mutation of mtDNA Maternally inherited retinitis pigmentosa, developmental delay, dementia, seizures, ataxia, proximal neurogenic muscle weakness and sensory neuropathy were described in four members of a family 33. Muscle biopsy showed no histochemical evidence of mitochondrial myopathy. Blood and muscle from the patients contained two populations of mtDNA, one of which had a previously unModels of mitochondrial genetic diseases and gene reported restriction site for the endonuclease A v a l . This was due to a point mutation at position 8993, therapy It should be possible to study the functional resulting in an amino acid change from a highly conserved leucine to arginine in subunit 6 of effects of mtDNA deletions and mutations in vitro mitochondrial H+-ATPase. There was a correlation using mitochonclrial transfection techniques. Isobetween both the presence and the severity of the lated human mitochondria, containing selectable disease, and the amount of mutant mtDNA in the mtDNA markers, have been introduced into cells that had their own mtDNA partly depleted. A rapid patients and their unaffected relatives. The o b s e r v a t i o n of mtDNA heteroplasmy in as- and virtually complete replacement of the recipient sociation with three human diseases (mitochondrial cell mtDNA was observed in most transformants 41. myopathies, LHON and the point mutation at Furthermore, human cell lines devoid of mtDNA position 8993 described above) is interesting. have been produced by prolonged exposure to low MtDNA heteroplasmy has not been described in concentrations of ethidium bromide, and mitochonhealthy subjects, despite the high mutation rate of dria containing mutant mtDNAs can be injected into mtDNA, which implies a need for heteroplasmy such cells 42. The potential for correcting mitochonduring the change from one genotype to another. drial genetic defects in cultured cells is attractive, but MtDNA heteroplasmy has been demonstrated in a the prospects of gene therapy in human mitochonsingle maternal line of Holstein cows 34 and it was drial diseases are hampered by the fact that the suggested that mtDNA could switch completely severely affected tissues (brain and muscle) contain from one genotype to another in a single generation nondividing cells 43. if the number of mtDNAs is greatly reduced at some point in oogenesis, as is likely to occur in maturing ova. Persistent heteroplasmy and deleterious Selected references 1 Anderson,S. et al. (1981) Nature 290, 457-465 mtDNA mutations might be related in some way. It 2 Chomyn, A. et aL (1985)in Achievements and Perspectives is possible that the rapid switch from one harmless of Mitochondrial Research (Biogenesis, VoL II) (Quagliariello, mtDNA type to another, which seems to occur E. et aL, eds), pp. 259-275, Elsevier 3 Cann, R. L., Stoneking, M. and Wilson, A. C. (1987) Nature during the evolution of possibly advantageous 325, 31-36 polymorphisms, does not take place when mtDNA 4 Petty, R. K. H., Harding, A. E. and Morgan-Hughes, J, A. mutations are harmful because of natural selection. (1986) Brain 109, 915-938 Survival would be less likely if these mutations were 5 DiMauro, S., Bonilla, E., Zeviani, M., Nakagawa, M. and DeVivo, D. C. (1985) Ann. NeuroL 17, 521-538 homoplasmic. 6 Harding, A. E., Petty, R. K. H. and Morgan-Hughes, J. A. (1988) J. Med. Genet. 28, 525-538 Other candidates for defects of mtDNA 7 Egger, J. and Wilson, J. (1983) New Engl. J. Med. 309, MtDNA defects have so far been described in 142-145 association with a wide range of clinical syndromes, 8 Holt, I. J., Harding, A. E. and Morgan-Hughes,J. A. (1988) Nature 331,717-719 and there are yet other possible candidates for mitochondrial genetic disease. Parkinson's disease is 9 Zeviani, M. etal. (1988) Neurology 38, 1339-1346 10 Moraes, C. T. et al. (1989) New Engl. J. Med. 320, a very speculative example. A selective deficiency of 1293-1299 complex I has been reported in the substantia nigra 11 Holt, I. J. etaL (1989)Ann. NeuroL 26, 699-708 and platelets of patients with this disease 35,36, 12 Poulton, J., Deadman, M. E. and Gardiner, R. M. (1989) Lancet i, 236-240 although more diffuse loss of respiratory chain 13 S. et al. (1990) Nucleic Acids Res. 18, 561-567 function (in muscle) has been suggested by 14 Mita, Nakase,H. etaL (1990)Am. J. Hum. Genet. 46, 418-427 others 37. Parkinson's disease is often familial, but a 15 Mira, S., Schmidt, B., Schon,E. A., DiMauro, S. and Bonilla, E. significant genetic component has been discounted (1989) Proc. Natl Acad. Sci. USA 86, 9509-9513 on the basis of similar concordance rates for the 16 Shoubridge,E. A., Karpati, G. and Hastings,E. M. (1990) Cell 62, 43-49 disorder in dizygotic and monozygotic twins. A 17 Rotig, A. et al. (1989) Lancet i, 902-903 heteroplasmic mtDNA defect is the only genetic 18 Pearson,H. A. etaL (1979)J. Pediatr. 95, 976-984 hypothesis entirely compatible with this 19 McShane,M. A. etaL (1991)Am. J. Hum. Genet. 48, 39-42 observation 36. When Southern blotting was used to 20 Rosing,H. S. etaL (1985)Ann. Neurol. 17, 228-237 TINS, Vol. 14, No. 4, 1991

Acknowledsernents Financialsupport was provided by the Brain Research Trustand the Muscular Oystrophy Croup of Great Bri~'n and Northern Ireland

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21 Shoffner, J. M. et aL (1990) Cell 61,931-937 22 Zeviani, M. etaL (1990)Am. J. Hum. Genet 47, 904-914 23 Goto, Y., Nonaka, I. and Horai, S. (1990) Nature 348, 651-653 24 Morgan-Hughes, J. A., Schapira, A. H. V., Cooper, J. M. and Clark, J. B. (1988) J. Bioenerg. Biomembranes 20, 365-382 25 Zeviani, M. et aL (1989) Nature 339, 309--311 26 Nikoskelainen, E. (1984) Neurology 34, 1482-1484 27 Wallace, D. C. etaL (1988)Science 242, 1427-1430 28 Holt, I. J., Miller, D. H. and Harding, A. E. (1989) J. Med. Genet. 26, 739-743 29 Vilkki, J., Savontaus, M-L. and Nikoskelainen, E. K. (1989) Am. J. Hum. Genet. 45, 206-211 30 Vilkki, J., Ott, J., Savontaus, M-L., Aula, P. and Nikoskelainen, E. K. Am. J. Hum. Genet. (in press) 31 Parker, W. D., Oley, C. A. and Parks, J. K. (1989) New Engl. J. Med. 320, 1331-1333 32 Howell, N. and McCullough, D. (1990) Am. J. Hum. Genet. 47, 629-634

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33 Holt, I. J., Harding, A. E., Petty, R. K. H. and Morgan-Hughes, J. A. (1990) Am. J. Hum. Genet. 46, 428-433 34 Hauswirth, W. W. and Laipis, P. J. (1985) in Achievements and Perspectives of Mitochondrial Research (Bio&enesis, Vol. II) (Quagliariello, E. et al., eds), pp. 49-60, Elsevier 35 Schapira, A. H. V. eta/. (1990)J. Neurochem. 54, 823-827 36 Parker, W. D., Boyson, S. J. and Parks, J. K. (1989) Ann. Neurol. 26, 719-723 37 Bindoff, L., Birch-Machin, M., Cartlidge, N. E. F., Parker, W. D. and Turnbull, D. M. (1989) Lancet ii, 49 38 Schapira, A. H. V. et aL (1990) Movement Disord. 5, 294-297 39 Ikebe, S. et al. (1990) Biochem. Biophys. Res, Commun. 170, 1044-1048 40 Linnane, A. W., Marzuki, S., Ozawa, T. and Tanaka, M. (1989) Lancet i, 642-645 41 King, M. P. and Attardi, G. (1988) Ce1152, 811-819 42 King, M. P. and Attardi, G. (1989) Science 246, 500-503 43 Lander, E. S. and Lodish, H. (1990) Cell 61,925-926

editor References

comprises the hippocampalseptal pathway, namely hippocampus to DLSN to MSN-NDB to SIR: hippocampus 5. In fact, recent In the article by Stewart and Fox~ lesion studies with ibotenic acid° 'Do septal neurons pace the concluded that the DLSN was hippocampal theta rhythm?' the critically involved in the generauthors show a certain degree of ation of hippocampal theta acuncertainty about the approtivity. Moreover, using an in vitro priateness of applying data obseptal slice preparation, we 7 have tained from non-primate mamobserved that DLSN neurons mals to humans. This reluctance is exhibit both bursting and singledue to the 'apparent absence of spike activity with a rhythmicity hippocampal theta rhythm from similar to the theta frequency. primates'. This statement is not This activity might serve as a correct. Hippocampal rhythmic direct 'pace-maker' or an indirect slow activity (RSA) or theta 'gate' in the processes that drive rhythm was incidentally observed rhythmic bursting in MSN-NDB in man by Giaquinto 2. Using Hippocampal RSA and neurons. Such an input would spectral analysis and radio-tel- DLSN neurons add an important relationship to emetry in order to record from SIR: the models proposed by Stewart freely behaving, epileptic patients Stewart and Fox ~ raised an im- and Fox, since others 8-I° have in whom chronically indwelling portant question in addition to demonstrated that the majority of serni-microelectrodes were surgi- that of their article's title. They MSN-NDB neurons do not cally implanted, we were able to stated that 'without additional exhibit intrinsic rhythmic bursting demonstrate RSA in humans 3. details of the interaction among activity. This hippocampal RSA indicated a septal cells, it is difficult to answer Thus, we suggest that cells in dominant low frequency (3-4 Hz) the question o f . . . how atropine- the DLSN be included as an inthat was modulated with move- sensitive cells are cholinergic tegral part of the septal oscillatory ment in a similar way to that of when they are the cells affected network proposed by Stewart and lower mammals. The relative dif- by atropine'. In fact, there are Foxl; these neurons could serve ficulty in demonstrating RSA in additional cholinoceptive cells the 'pace-maker' function for the human hippocampus 4 might within the septum other than theta rhythm within the hippobe due to the decrease in RSA those of the medial septal nucleus campal-septal pathway. amplitude and regularity in higher and the nucleus of the diagonal J. P. Gallagher primates 5. It is therefore necess- band (MSN-NDB) that appear to /H. J. Twery ary to use computer analysis play a central role in the oscil- The Universityof TexasMedical Branch, Room methods in recording from freely latory network envisioned by 1.101, PharmacologyBuilding, Galveston, TX behaving subjects in order to Stewart and Fox. 77550-2782, USA. detect hippocarnpal RSA in These cells lie within the dorsohumans. We must conclude that lateral septal nucleus (DLSN), are the human hippocampus is no most likely GABAergic 2, and ex- References exception among mammals with hibit both atropine-sensitive 3 and 1 Stewart, M. and Fox, S. E. (1990) regard to the ability to display -resistant 4 responses to cholinTrends Neurosci. 13, 163-168 RSA. 20nteniente, B., Tago, H., Kirnura, H. ergic receptor stimulation. The and Maeda, T. (1986) J. Comp. F. H. Lopes da Silva extensive projection of DLSN NeuroL 248, 422--430 neurons to the MSN-NDB has Dept Experimental Zoology, University of 3 Hasuo, H. Gallagher, J. P. and Amsterdam, Kruislaan320, 1098 SM Amster- long been considered a key link in Shinnick-Gallagher, P. (1988) Brain dam The Netherlands. the three-neuron circuit that Res. 438, 323-327

Hippocampal RSA in humans

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I Stewart, M. and Fox, S. E. (1990) Trends Neurosci. 13, 163-168 2 Giaquinto, S. (1973) Confin. Neurol. 35, 285-303 3 Arnolds, D. E. A. T., Lopes da Silva, F. G., Aitink, W., Kamp, A. and Boeijinga, P. (1980) ElectroencephaIogr. C/in. Neurophysiol. 50, 324-328 4 Halgren, E., Babb, T. L. and Crandall, P. H. (1978) Electroencephalogr. Clin. Neurophysiol. 44, 778-781 5 Crowne, D. P. and Radcliffe, D. D. (1975) in The Hippocampus (Vol. 2) (Isaacson, R. L. and Pribrarn, K. H., eds), pp. 185-203, Plenum Press

TINS, VoL 14, No. 4, 1991

Neurological disease and mitochondrial genes.

Mitochondria contain 2-10 copies of a small, double-stranded, circular DNA molecule that is exclusively maternally transmitted. Until recently, the on...
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