Acta Neuropathologica

, Volume 124, Issue 5, pp 749–760

Coexistence of Huntington’s disease and amyotrophic lateral sclerosis: a clinicopathologic study

  • Mari Tada
  • Elizabeth A. Coon
  • Alexander P. Osmand
  • Patricia A. Kirby
  • Wayne Martin
  • Marguerite Wieler
  • Atsushi Shiga
  • Hiroe Shirasaki
  • Masayoshi Tada
  • Takao Makifuchi
  • Mitsunori Yamada
  • Akiyoshi Kakita
  • Masatoyo Nishizawa
  • Hitoshi Takahashi
  • Henry L. Paulson
Original Paper

DOI: 10.1007/s00401-012-1005-5

Cite this article as:
Tada, M., Coon, E.A., Osmand, A.P. et al. Acta Neuropathol (2012) 124: 749. doi:10.1007/s00401-012-1005-5

Abstract

We report a retrospective case series of four patients with genetically confirmed Huntington’s disease (HD) and sporadic amyotrophic lateral sclerosis (ALS), examining the brain and spinal cord in two cases. Neuropathological assessment included a polyglutamine recruitment method to detect sites of active polyglutamine aggregation, and biochemical and immunohistochemical assessment of TDP-43 pathology. The clinical sequence of HD and ALS varied, with the onset of ALS occurring after the mid-50’s in all cases. Neuropathologic features of HD and ALS coexisted in both cases examined pathologically: neuronal loss and gliosis in the neostriatum and upper and lower motor neurons, with Bunina bodies and ubiquitin-immunoreactive skein-like inclusions in remaining lower motor neurons. One case showed relatively early HD pathology while the other was advanced. Expanded polyglutamine-immunoreactive inclusions and TDP-43-immunoreactive inclusions were widespread in many regions of the CNS, including the motor cortex and spinal anterior horn. Although these two different proteinaceous inclusions coexisted in a small number of neurons, the two proteins did not co-localize within inclusions. The regional distribution of TDP-43-immunoreactive inclusions in the cerebral cortex partly overlapped with that of expanded polyglutamine-immunoreactive inclusions. In the one case examined by TDP-43 immunoblotting, similar TDP-43 isoforms were observed as in ALS. Our findings suggest the possibility that a rare subset of older HD patients is prone to develop features of ALS with an atypical TDP-43 distribution that resembles that of aggregated mutant huntingtin. Age-dependent neuronal dysfunction induced by mutant polyglutamine protein expression may contribute to later-life development of TDP-43 associated motor neuron disease in a small subset of patients with HD.

Keywords

Huntington’s diseaseAmyotrophic lateral sclerosisPolyglutamineTDP-43

Supplementary material

401_2012_1005_MOESM1_ESM.docx (71 kb)
Supplementary material 1 (DOCX 70 kb)

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Mari Tada
    • 1
    • 2
    • 3
  • Elizabeth A. Coon
    • 4
  • Alexander P. Osmand
    • 5
  • Patricia A. Kirby
    • 6
  • Wayne Martin
    • 7
  • Marguerite Wieler
    • 7
  • Atsushi Shiga
    • 3
  • Hiroe Shirasaki
    • 8
  • Masayoshi Tada
    • 2
  • Takao Makifuchi
    • 9
  • Mitsunori Yamada
    • 10
  • Akiyoshi Kakita
    • 3
  • Masatoyo Nishizawa
    • 2
  • Hitoshi Takahashi
    • 3
  • Henry L. Paulson
    • 1
  1. 1.Department of NeurologyUniversity of Michigan Health SystemAnn ArborUSA
  2. 2.Department of Neurology, Brain Research InstituteUniversity of NiigataNiigataJapan
  3. 3.Department of Pathology, Brain Research InstituteUniversity of NiigataNiigataJapan
  4. 4.Department of NeurologyMayo ClinicRochesterUSA
  5. 5.Department of MedicineUniversity of Tennessee Graduate School of MedicineKnoxvilleUSA
  6. 6.Department of PathologyUniversity of Iowa Carver College of MedicineIowa CityUSA
  7. 7.Division of NeurologyUniversity of AlbertaAlbertaCanada
  8. 8.Shirasaki ClinicToyamaJapan
  9. 9.Department of Clinical ResearchJoetsu General HospitalNiigataJapan
  10. 10.Department of Clinical Research, National Hospital OrganizationSaigata National HospitalNiigataJapan