Huntington's Disease

By: Carolyn L. Crankshaw, BioFiles v7 n2, 2011, 9–14

BioFiles Volume 7, Number 2 — Neurodegenerative Diseases

Download BioFiles v7 n2 (13.0 Mb PDF)

Huntington's disease (HD) is an autosomal dominant, late-onset neurodegenerative disorder characterized by a selective neuronal cell death in the cortex and striatum leading to cognitive dysfunction, motor impairment and behavioral changes. The underlying cause of HD is the expansion of a CAG repeat located within the first exon of the Huntingtin gene (HTT). In persons with HD, the HTT gene is found to contain 36 or more CAG repeats, resulting in a mutant form of the Huntingtin protein. The current hypothesis in HD is that neuronal degeneration results from the combined effects of a gain-of-function in the mutated form of HTT along with a loss of function in the wild-type HTT. Pathogenesis in HD appears to involve different mechanisms.

  1. HD mutation is translated into an expanded polyglutamine tract (polyQ) that induces conformational changes and abnormal folding in the mutated Huntingtin. These insoluble proteins accumulate as ubiquitinated cytoplasmic perinuclear aggregates. The resulting perinuclear inclusions impair the ubiquitinproteasome system, leading to the accumulation of more misfolded proteins and cell death.
  2. HTT mutation results in abnormal protein interactions. For example, mutant Huntingtin interferes with the binding of disks large associated protein 4 (DLGAP4) to the glutamate receptor NMDAR1 (GRIN1). This results in receptor hypersensitivity, an influx of Ca2+, and excitotoxicity. Additionally, increased Ca2+ levels activate caspases leading to cell apoptosis, cleavage of mutant Huntingtin, and the generation of toxic N-terminal fragments. In HD, mutant Huntingtin can also inhibit transcription by failing to bind to the repressor REST in the cytoplasm. This results in an accumulation of the repressor in the nucleus and inhibition of brain-derived neurotrophic factor (BDNF) transcription, which is an important survival factor for striatal neurons. Finally, decreased binding between mutant Huntingtin and proteins such as MLK2 (MAP3K10), HIP1, and HIP14 leads to apoptotic cell death, impaired vesicle trafficking and endocytosis.
  3. Huntingtin mutation leads to aggregate sequestration of various proteins, including transcription factors. Proteolytically cleaved N-terminal fragments of mutated Huntingtin can translocate into the nucleus to form neuronal intranuclear inclusions. Once there, mutated Huntingtin recruits transcription factors such as CBP (CREBBP, EP300), TBP and SIN3A which disrupt gene transcription leading to neurodegeneration.




  1. Hu, Y., et al. Bcl-XL interacts with Apaf-1 and inhibits Apaf-1-dependent caspase-9 activation. Proc. Natl. Acad. Sci. USA. 1998, 95, 4386-4391.
  2. Rangone, H., et al. The serum- and glucocorticoidinduced kinase SGK inhibits mutant Huntingtininduced toxicity by phosphorylating serine 421 of Huntingtin. Eur. J. Neurosci. 2004, 19, 273-279.
  3. Nakagawa, T. and Yuan, J. Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J. Cell. Biol. 2000, 150, 887-894.
  4. Heumann, R., et al. Transgenic activation of Ras in neurons promotes hypertrophy and protects from lesion-induced degeneration. J. Cell. Biol. 2000, 151, 1537-1548.
  5. Weber, M.M., et al. Rat somatotroph insulin-like growth factor-II (IGF-II) signaling: role of the IGF-I receptor. Endocrinology. 1992, 131, 2147-2153.
  6. Liu, Y.F., et al. SH3 domain-dependent association of Huntingtin with epidermal growth factor receptor signaling complexes. J. Biol. Chem. 1997, 272, 8121-8124.
  7. Perkins, C.L., et al. The role of Apaf-1, caspase-9, and bid proteins in etoposide- or paclitaxel-induced mitochondrial events during apoptosis. Cancer Res. 2000, 60, 1645-1653.
  8. Tartare-Deckert, S., et al. Interaction of the molecular weight 85K regulatory subunit of the phosphatidylinositol 3-kinase with the insulin receptor and the insulinlike growth factor-1 (IGF- I) receptor: comparative study using the yeast two-hybrid system. Endocrinology. 1996, 137, 1019-1024.
  9. Doonan, F., et al. Caspase-Independent Photoreceptor Apoptosis in Mouse Models of Retinal Degeneration. J. Neurosci. 2003, 23, 5723-5731.
  10. Liu, Y.F., et al. Activation of MLK2-mediated signaling cascades by polyglutamine-expanded Huntingtin. J. Biol. Chem. 2000, 275, 19035-19040.
  11. Borg J.P., et al. The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein. Mol. Cell. Biol. 1996, 16, 6229-6241.
  12. Petrosillo, G., et al. Ca2+-induced Reactive Oxygen Species Production Promotes Cytochrome c Release from Rat Liver Mitochondria via Mitochondrial Permeability Transition (MPT)-dependent and MPT-independent Mechanisms: role of cardiolipin. J. Biol. Chem. 2004, 279, 53103-53108.
  13. Adler, V., et al. Complexes of p21RAS with JUN N-terminal kinase and JUN proteins. Proc. Natl. Acad. Sci. USA. 1995, 92, 10585-10589.
  14. Thien, C.B. and Langdon, W.Y. Tyrosine kinase activity of the EGF receptor is enhanced by the expression of oncogenic 70Z-Cbl. Oncogene. 1997, 15, 2909-2919.
  15. Yazgan, O., and Pfarr, C.M. Regulation of two JunD isoforms by Jun-N-terminal kinases. J. Biol. Chem. 2002, 277, 29710-29718.
  16. Hirai, S., et al. MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of c-Jun N-terminal kinase/ stress-activated protein kinase. J. Biol. Chem. 1997, 272, 15167-15173.
  17. Hattori, S., et al. Activation of mitogen-activated protein kinase and its activator by ras in intact cells and in a cell-free system. J. Biol. Chem. 1992, 267, 20346-20351.
  18. Montcouquiol, M. and Corwin, J.T. Intracellular signals that control cell proliferation in mammalian balance epithelia: key roles for phosphatidylinositol-3 kinase, mammalian target of rapamycin, and S6 kinases in preference to calcium, protein kinase C, and mitogenactivated protein kinase. J. Neurosci. 2001, 21, 570-580.
  19. Juliano, R.L., Signal transduction by cell adhesion receptors and the cytoskeleton: functions of integrins, cadherins, selectins, and immunoglobulin-superfamily members. Annu. Rev. Pharmacol. Toxicol. 2002, 42, 283-323.
  20. Rosales, J.L., et al., GTP-dependent secretion from neutrophils is regulated by Cdk5. J. Biol. Chem. 2004, 279, 53932-53936.
  21. Shibuya, M., Structure and function of VEGF/VEGFreceptor system involved in angiogenesis. Cell Struct. Funct. 2001, 26, 25-35.
  22. Gafni, J., et al., Inhibition of Calpain Cleavage of Huntingtin Reduces Toxicity: accumulation of calpain/caspase fragments in the nucleus. J. Biol. Chem. 2004, 279, 20211-20220.


Related Links