Advertisement

Acta Neuropathologica

, Volume 114, Issue 6, pp 633–639 | Cite as

Mitochondrial alterations in dorsal root ganglion cells in sporadic amyotrophic lateral sclerosis

  • Shoichi Sasaki
  • Yoshiharu Horie
  • Makoto Iwata
Original Paper

Abstract

Little information is available regarding the morphological changes in the mitochondria in amyotrophic lateral sclerosis (ALS). In particular, mitochondrial changes in dorsal root ganglion cells have not yet been examined. We therefore conducted an electron microscopic examination of the mitochondria in dorsal root ganglion cells in 11 sporadic ALS patients, and 12 age-matched, non-neurological control individuals in order to determine whether or not they are affected in ALS. In both the controls and ALS patients, unusual inclusion bodies were frequently observed in the mitochondria in the somata of the ganglion cells. The inclusions consisted of an aggregate of tubules measuring approximately 40 nm in diameter varying in size and number. Such inclusions were frequently present in the cristae and/or intermembrane space, often expanding to form large bundles in the dilated intermembrane space. These structures quite frequently protruded outward unilaterally or bilaterally and were partially surrounded by the outer membrane of the mitochondria. The number of inclusions was significantly higher in the ALS patients than in the controls (P < 0.0001). Regularly spaced transverse processes similar to the rungs of a ladder were occasionally observed in the intermembrane space, along with infrequent but markedly increased cristae and stubby mitochondria. We concluded that mitochondrial abnormalities may be involved in the degenerative processes in the dorsal root ganglion cells in sporadic ALS. These findings therefore suggest that ALS is a widespread, more generalized disorder than previously thought, and that the degeneration is not confined to the motor neuron system.

Keywords

Amyotrophic lateral sclerosis Motor neuron disease Dorsal root ganglia Mitochondria Inclusion bodies Intermembrane space Ultrastructure 

Notes

Acknowledgments

This work was supported by a Grant-in-Aid for General Scientific Research (C) from the Japanese Ministry of Education, Science and Culture. The authors thank Prof. A. Hirano (Division of Neuropathology, Montefiore Medical Center, New York, NY, USA) for his many valuable comments and suggestions.

References

  1. 1.
    Bowling AC, Schulz JB, Brown RH, Beal MF (1993) SOD activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic ALS. J Neurochem 61:2322–2325PubMedCrossRefGoogle Scholar
  2. 2.
    Brownell B, Oppenheimer DR, Hughes JT (1970) The central nervous system in motor neurone disease. J Neurol Neurosurg Psychiatr 33:338–357PubMedCrossRefGoogle Scholar
  3. 3.
    Curti D, Malaspina A, Facchetti G, Camana C, Mazzini L, Tosca P, Zerbi F, Ceroni M (1996) Amyotrophic lateral sclerosis: oxidative energy metabolism and calcium homeostasis in peripheral blood lymphocytes. Neurology 47:1060–1064PubMedGoogle Scholar
  4. 4.
    Dal Canto MC, Gurney ME (1995) Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu, Zn SOD, and in mice overexpressing wild-type human SOD: a model of familial amyotrophic lateral sclerosis (FALS). Brain Res 676:25–40PubMedCrossRefGoogle Scholar
  5. 5.
    Dhaliwal GK, Grewall RP (2000) Mitochondrial DNA deletion mutation levels are elevated in ALS brains. Neuroreport 11:2507–2509PubMedCrossRefGoogle Scholar
  6. 6.
    Dyck PJ, Stevens JC, Mulder DW, Espinosa RE (1975) Frequency of nerve fiber degeneration of peripheral motor and sensory neurons in amyotrophic lateral sclerosis: morphometry of deep and superficial peroneal nerves. Neurology 25:781–787PubMedGoogle Scholar
  7. 7.
    Hirano A, Donnenfeld H, Sasaki S, Nakano I (1984) Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 43:461–470PubMedGoogle Scholar
  8. 8.
    Jaarsma D, Rognoni F, Duijn W, van Verspaget HW, Haasdijk ED, Holstege JC (2001) CuZn superoxide dismutase (SOD1) accumulates in vacuolated mitochondria in transgenic mice expressing amyotrophic lateral sclerosis-linked SOD1 mutations. Acta Neuropathol 102:293–305PubMedGoogle Scholar
  9. 9.
    Kong J, Xu Z (1998) Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci 18:3241–3250PubMedGoogle Scholar
  10. 10.
    Lawyer T, Netsky MG (1953) Amyotrophic lateral sclerosis: a clinico-anatomic study of 53 cases. Arch Neurol 69:171–192Google Scholar
  11. 11.
    Matsui Y, Mozai T, Kakehi K (1985) Functional and morphometric study of the liver in motor neuron disease. J Neurol 232:15–19CrossRefGoogle Scholar
  12. 12.
    Nakano K, Hirayama K, Terao K (1987) Hepatic ultrastructural changes and liver dysfunction in amyotrophic lateral sclerosis. Arch Neurol 44:103–106PubMedGoogle Scholar
  13. 13.
    Page RW, Moskowitz RW, Nash RE, Roessmann U (1977) Lower motor neuron disease with spinocerebellar degeneration. Ann Neurol 2:524–530PubMedCrossRefGoogle Scholar
  14. 14.
    Peña CE (1977) Virus-like particles in amyotrophic lateral sclerosis: electron microscopical study of a case. Ann Neurol 1:290–297PubMedCrossRefGoogle Scholar
  15. 15.
    Peña CE (1980) Periodic units in the intracristal and envelope spaces of neuronal mitochondria. An artifact due to delayed fixation. Acta Neuropathol 51:249–250PubMedCrossRefGoogle Scholar
  16. 16.
    Sasaki S, Hirano A (1983) Study of intracytoplasmic acidophilic granules in the human dorsal root ganglia. Neurol Med (Tokyo) 19:263–268Google Scholar
  17. 17.
    Sasaki S, Iwata M (1996) Impairment of fast axonal transport in the proximal axons of anterior horn neurons in amyotrophic lateral sclerosis. Neurology 47:535–540PubMedGoogle Scholar
  18. 18.
    Sasaki S, Iwata M (1996) Ultrastructural study of synapses in the anterior neurons of patients with amyotrophic lateral sclerosis. Neurosci Lett 204:53–56PubMedCrossRefGoogle Scholar
  19. 19.
    Sasaki S, Iwata M (2007) Mitochondrial alterations in the spinal cord of patients with sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 66:10–16PubMedCrossRefGoogle Scholar
  20. 20.
    Sasaki S, Maruyama S (1993) A fine structural study of Onuf’s nucleus in sporadic amyotrophic lateral sclerosis. J Neurol Sci 119:28–37PubMedCrossRefGoogle Scholar
  21. 21.
    Sasaki S, Tsutsumi Y, Yamane K, Sakuma H, Maruyama S (1992) Sporadic amyotrophic lateral sclerosis with extensive neurological involvement. Acta Neuropathol 84:211–215PubMedCrossRefGoogle Scholar
  22. 22.
    Sasaki S, Warita H, Murakami T, Abe K, Iwata M (2004) Ultrastructural study of mitochondria in the spinal cord of transgenic mice with a G93A mutant SOD1 gene. Acta Neuropathol 107:461–474PubMedCrossRefGoogle Scholar
  23. 23.
    Siklos L, Engelhardt J, Harati Y, Smith RG, Joo F, Appel SH (1996) Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophic lateral sclerosis. Ann Neurol 39:203–216PubMedCrossRefGoogle Scholar
  24. 24.
    Takahashi H, Oyanagi K, Ohhama E, Ikuta F (1992) Clarke’s column in sporadic amyotrophic lateral sclerosis. Acta Neuropathol 84:465–470PubMedCrossRefGoogle Scholar
  25. 25.
    Wiedemann FR, Manfredi G, Mawrin C, Beal MF, Schon EA (2002) Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients. J Neurochem 80:616–625PubMedCrossRefGoogle Scholar
  26. 26.
    Wong PC, Pardo CA, Borchelt DR, Lee MK, Copeland NG, Jenkins NA, Sisodia SS, Cleveland DW, Price DL (1995) An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14:1105–1116PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Department of Neurology, Neurological InstituteTokyo Women’s Medical UniversityTokyoJapan
  2. 2.Division of BiostatisticsKitasato University Graduate SchoolTokyoJapan

Personalised recommendations