Acta Neuropathologica

, Volume 121, Issue 4, pp 487–498 | Cite as

Modulation of lipid peroxidation and mitochondrial function improves neuropathology in Huntington’s disease mice

  • Junghee Lee
  • Bela Kosaras
  • Steve J. Del Signore
  • Kerry Cormier
  • Ann McKee
  • Rajiv R. Ratan
  • Neil W. Kowall
  • Hoon Ryu
Original Paper


Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. Oxidative damage has been associated with pathological neuronal loss in HD. The therapeutic modulation of oxidative stress and mitochondrial function using low molecular weight compounds may be an important strategy for delaying the onset and slowing the progression of HD. In the present study, we found a marked increase of 4-hydroxy-2-nonenal (4-HNE) adducts, a lipid peroxidation marker, in the caudate and putamen of HD brains and in the striatum of HD mice. Notably, 4-HNE immunoreactivity was colocalized with mutant huntingtin inclusions in the striatal neurons of R6/2 HD mice. Administration of nordihydroguaiaretic acid (NDGA), an antioxidant that functions by inhibiting lipid peroxidation, markedly reduced 4-HNE adduct formation in the nuclear inclusions of R6/2 striatal neurons. NDGA also protected cultured neurons against oxidative stress-induced cell death by improving ATP generation and mitochondrial morphology and function. In addition, NDGA restored mitochondrial membrane potential, mitochondrial structure, and synapse structure in the striatum of R6/2 mice and increased their lifespan. The present findings suggest that further therapeutic studies using NDGA are warranted in HD and other neurodegenerative diseases characterized by increased oxidative stress and altered mitochondrial function.


Huntington’s disease Mitochondria Lipid peroxidation 4-Hydroxy-2-nonenal (4-HNE) Neuronal survival 



We thank to Katharine Karr and Yu Jin Hwang for the preparation of manuscript. This study was supported by NIH NS52724 (H.R.).

Supplementary material

401_2010_788_MOESM1_ESM.doc (2.2 mb)
Supplementary material 1 (DOC 2,268 kb)


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Junghee Lee
    • 1
    • 2
  • Bela Kosaras
    • 3
  • Steve J. Del Signore
    • 1
    • 4
  • Kerry Cormier
    • 1
    • 4
  • Ann McKee
    • 1
    • 4
  • Rajiv R. Ratan
    • 5
  • Neil W. Kowall
    • 1
    • 2
  • Hoon Ryu
    • 1
    • 2
  1. 1.Department of Neurology and PathologyBoston University School of MedicineBostonUSA
  2. 2.VA Boston Healthcare SystemBostonUSA
  3. 3.Department of NeurologyBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonUSA
  4. 4.Bedford VA Medical CenterBedfordUSA
  5. 5.Department of NeurologyWeill Medical College of Cornell University, Burke-Cornell Medical Research InstituteWhite PlainsUSA

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