. 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.


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  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.


    . 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.

    View all comments by Peggy Nopoulos

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  1. In Mice, Huntingtin Defects Start in the Womb