The debilitating symptoms of Huntington disease typically manifest in people’s thirties and forties, but scientists have found that more subtle problems occur earlier. Now, a study published online December 2 in PNAS pushes the neural defects all the way back to embryos. First author Aldrin Molero, principal investigator Mark Mehler, and colleagues at Albert Einstein College of Medicine in Bronx, New York, found multiple abnormalities in the neural development of Huntington’s model mice expressing the disease-causing multiple glutamine repeats from the aberrant huntingtin gene.

While the research does not necessarily mean that the developmental defects are relevant to human disease, it hints that mutant huntingtin trips up the brain’s formation in ways that render neurons more susceptible to the environmental stressors that come with aging. If true, “it really reorients our thinking about Huntington disease,” said Christopher Ross of Johns Hopkins University in Baltimore, Maryland, who was not involved with the study. Ross compared the theory to the “two-hit hypothesis” from cancer research: the first hit could be minor developmental defects caused by mutant huntingtin, which do not cause problems until a second hit, such as the oxidative damage associated with aging, triggers neurodegeneration and disease.

Mehler first theorized, nearly 10 years ago, that the proteins associated with neurodegenerative disease, such as huntingtin, presenilins, and amyloid-β precursor protein (APP), might cause developmental problems leading to eventual diseases of aging (Mehler and Gokhan, 2000; Mehler and Gokhan, 2001). He selected Huntington’s as the first disease to investigate because of the clear genetic cause and availability of good animal models.

Since the initial theory papers, several other reports have suggested that mutant huntingtin affects the body before full-blown Huntington’s appears. Researchers in the multicenter PREDICT-HD trial, studying healthy people who carry glutamine-expanded huntingtin, have found issues such as motor problems (Biglan et al., 2009), changes in brain anatomy (Klöppel et al., 2009), and behavioral symptoms (Beglinger et al., 2008) before the onset of what are considered characteristic HD symptoms. Others have observed cognitive problems before the disease asserts itself (Robins Wahlin et al., 2007). Huntingtin’s role in development is also apparent in knockout mice, where early embryo patterning is altered (Woda et al., 2005).

It took Mehler and Molero seven years to assemble their data. They knew that if their theory was correct, any defects caused by mutant huntingtin were likely to be subtle. The researchers compared two knock-in mouse lines in which the first exon of endogenous huntingtin was replaced with the equivalent human exon with either 18 or 111 glutamine repeats. Hdh-18 represents the wild-type and Hdh-111 the mutant form of the protein. Molero and colleagues analyzed several aspects of the formation of medium spiny neurons in embryos, focusing on the striatum, a part of the brain involved in motor function that is affected in HD.

The researchers found that there were many, many things wrong with the Hdh-111 embryos. “The range of deficits was extraordinary,” Mehler said. “We saw deficits across the board.” Formation of the striatum appeared to be delayed. Under the microscope, the researchers saw reduced expression of medium spiny neuron markers such as Islet1 and NeuN, compared with Hdh-18 embryos of the same age. DARP-32 and mGluR1, which showed a patchy distribution in the Hdh-18 embryos, were more diffuse in the Hdh-111 embryos. To analyze cell division, they tagged the embryos’ DNA with BrdU, which is diluted with each passing cell division. Progenitor cells in the striatal region were slow to exit the cell cycle and differentiate. These cells also overexpressed pluripotency markers such as Sox2 and Nanog, which may have caused the delay in maturation. “One of the things that is most remarkable is, given how many changes we find, the fact that homeostasis can be maintained,” Mehler said.

The authors suspect that minor developmental changes make medium spiny neurons in the striatum extra susceptible to environmental stressors later in life. “Adult life is essentially a toxic state for the brain,” Mehler said. Cellular stresses that normal cells can handle—such as DNA damage, oxidative stress, or dysregulation of the proteosomal pathway—might be enough to tip these cells toward degeneration.

“The fact that we have discovered these abnormalities doesn’t necessarily say that they relate to pathogenesis,” Mehler said. “We have in no way established that there is a causative link.”

Stan Lazic of Roche Pharmaceuticals in Basel, Switzerland, was skeptical of the link between early developmental defects and eventual neurodegeneration. “If these differences occur so much earlier than the onset of symptoms (about 40 years earlier, if we extrapolate to human disease), then these aren’t the important differences!” he wrote in an e-mail to ARF. “Young pre-symptomatic individuals with the HD gene are relatively normal, so if developmental differences exist, their role is likely to be relatively minor in light of the massive cell death that these patients experience later in life.”

The clear next step is to examine striatal development in other HD models, in adult animals as well as in people. “If the same results are found in other animal models, then it is more likely that similar differences would be found in the human condition,” Lazic wrote.

Mehler is also looking into the possibility that there are developmental defects in other models of neurodegenerative disease. APP and PS1, which cause early-onset familial Alzheimer disease when mutated, have both been linked to neurodevelopment in mammals (see ARF related news story and Eder-Colli et al., 2009).—Amber Dance.

Reference:
Molero AE, Gokhan S, Gonzalez S, Feig JL, Alexandre LC, Mehler MF. Impairment of developmental stem cell-mediated striatal neurogenesis and pluripotency genes in a knock-in model of Huntington’s disease. PNAS 2009 Dec 2. Abstract

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

  1. The paper by Molero et al. is an excellent study that builds on previous work to steadily support a somewhat heretic notion: that degenerative brain disorders are, in fact, neurodevelopmental disorders in which the key pathoetiology is that of abnormal development. Studies supporting this theory have come from several areas of research (both clinical and basic science) as well as from a variety of diseases including Alzheimer's, Parkinson's, Huntington's, and the polyglutamine diseases such as the spinal cerebellar ataxias (SCAs). One study that supports this theory (Serra et al., 2006) shows that in a mouse model of SCA type 1, the motor phenotype and histologic abnormalities of the cerebellum are much more severe if the mutant protein, ataxin 1 (ATXN1), is expressed during development. If it is expressed after development, the phenotype and histology are substantially less. Therefore, not only is abnormal development a part of the etiology, it is a vital part. Also, as mentioned in the Molero article, clinical studies of subjects with Huntington's, who are known to have a polyglutamine expanded gene but are over 20 years from developing the disease, show brain abnormalities that are more likely due to abnormal development rather than prolonged degeneration (Paulsen et al., 2006 and Nopoulos et al., 2007).

    It is time for the field of degenerative brain disorders to have a conceptual frame-shift. In particular, if these diseases are to be ”cured” or prevented, then focusing on the degenerative phase of the disease may not be as effective as understanding the origins of the disorders in the context of abnormal development.

    References:

    . RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell. 2006 Nov 17;127(4):697-708. PubMed.

    . Brain structure in preclinical Huntington's disease. Biol Psychiatry. 2006 Jan 1;59(1):57-63. PubMed.

    . Morphology of the cerebral cortex in preclinical Huntington's disease. Am J Psychiatry. 2007 Sep;164(9):1428-34. PubMed.

Comments on Primary Papers for this Article

No Available Comments on Primary Papers for this Article

References

News Citations

  1. San Diego: Exploring the Function of APP, Part 1

Paper Citations

  1. . Mechanisms underlying neural cell death in neurodegenerative diseases: alterations of a developmentally-mediated cellular rheostat. Trends Neurosci. 2000 Dec;23(12):599-605. PubMed.
  2. . Developmental mechanisms in the pathogenesis of neurodegenerative diseases. Prog Neurobiol. 2001 Feb;63(3):337-63. PubMed.
  3. . Motor abnormalities in premanifest persons with Huntington's disease: the PREDICT-HD study. Mov Disord. 2009 Sep 15;24(12):1763-72. PubMed.
  4. . Automatic detection of preclinical neurodegeneration: presymptomatic Huntington disease. Neurology. 2009 Feb 3;72(5):426-31. PubMed.
  5. . Obsessive and compulsive symptoms in prediagnosed Huntington's disease. J Clin Psychiatry. 2008 Nov;69(11):1758-65. PubMed.
  6. . Early cognitive deficits in Swedish gene carriers of Huntington's disease. Neuropsychology. 2007 Jan;21(1):31-44. PubMed.
  7. . Inactivation of the Huntington's disease gene (Hdh) impairs anterior streak formation and early patterning of the mouse embryo. BMC Dev Biol. 2005;5:17. PubMed.
  8. . The presenilin-1 familial Alzheimer's disease mutation P117L decreases neuronal differentiation of embryonic murine neural progenitor cells. Brain Res Bull. 2009 Oct 28;80(4-5):296-301. PubMed.
  9. . Impairment of developmental stem cell-mediated striatal neurogenesis and pluripotency genes in a knock-in model of Huntington's disease. Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21900-5. PubMed.

External Citations

  1. PREDICT-HD trial

Further Reading

Papers

  1. . Selective neuronal requirement for huntingtin in the developing zebrafish. Hum Mol Genet. 2009 Dec 15;18(24):4830-42. PubMed.
  2. . Altered CB1 receptor and endocannabinoid levels precede motor symptom onset in a transgenic mouse model of Huntington's disease. Neuroscience. 2009 Sep 29;163(1):456-65. PubMed.
  3. . Extensive early motor and non-motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington's disease mice. Neuroscience. 2008 Nov 11;157(1):280-95. PubMed.
  4. . A progressive and cell non-autonomous increase in striatal neural stem cells in the Huntington's disease R6/2 mouse. J Neurosci. 2006 Oct 11;26(41):10452-60. PubMed.
  5. . Impaired learning-dependent cortical plasticity in Huntington's disease transgenic mice. Neurobiol Dis. 2004 Dec;17(3):427-34. PubMed.
  6. . Detection of early behavioral markers of Huntington's disease in R6/2 mice employing an automated social home cage. Behav Brain Res. 2009 Nov 5;203(2):188-99. PubMed.
  7. . Impairment of developmental stem cell-mediated striatal neurogenesis and pluripotency genes in a knock-in model of Huntington's disease. Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21900-5. PubMed.

News

  1. A Toxic Combo: Huntingtin Specificity Tied to Striatal G Protein
  2. BDNF the Next AD Gene Therapy?
  3. Huntingtin Protein’s First Act: Overexciting Synapses
  4. San Diego: Exploring the Function of APP, Part 1

Primary Papers

  1. . Impairment of developmental stem cell-mediated striatal neurogenesis and pluripotency genes in a knock-in model of Huntington's disease. Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21900-5. PubMed.