Editors' ChoiceMedicine

Early Meeting Sets the Fate

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Science Translational Medicine  18 Aug 2010:
Vol. 2, Issue 45, pp. 45ec129
DOI: 10.1126/scitranslmed.3001568

As common neuropsychiatric disorders with limited treatment options, Alzheimer’s disease and schizophrenia have massive public health implications and take their toll on patients and their caretakers alike. Although the etiologies, ages of onset, and disease courses of these illnesses are clearly divergent, physicians and scientists have noted some clinical similarities that result from widespread cortical dysfunction. These include memory loss, social disturbances, and erosion of identity and autonomy. A key to the pathophysiology of Alzheimer’s disease is thought to be the proteolysis of β-amyloid precursor protein (APP) to Aβ (amyloid-β protein), which is a hallmark of the disease. Although no comparable hallmark has yet been identified in schizophrenia, several candidate genes have been associated with the illness. This list notably includes the Disrupted-in-Schizophrenia 1 gene (DISC1), which encodes DISC1, a protein that has important roles in neural proliferation, migration, and neurite outgrowth. Now, Young-Pearse and colleagues have linked APP and DISC1 in cortical development.

Using electroporation to introduce APP- or DISC1-related short-hairpin RNAs (shRNAs) (to knock down endogenous APP or DISC1, respectively) into normal fetal rat brains in utero, the authors found that co-electroporation of an expression vector that encoded full-length wild-type human DISC1 protein rescued the deleterious effects of APP knockdown on cell migration into the cortical plate. In contrast, expression of the APP protein in rat brains in utero did not rescue DISC1 knockdown. Furthermore, knockdown of the APP or DISC1 proteins did not have any effect on cell proliferation. APP knockdown did, however, alter localization of the DISC1 protein, to diffuse immunoreactivity within the cell body of neurons, versus intense focal immunoreactivity primarily in the neurons’ centrosomes—the cell’s microtubule-organizing organelle—in control preparations. Western immunoblots that were used to identify patterns of coimmunoprecipitation in transfected COS cells (a monkey kidney cell line) and normal adult rat brain tissue indicated that DISC1 can form complexes with APP. In these cells, endogenous DISC1 was localized to multiple subcellular compartments, with only a small portion present in the membrane fraction, suggesting that the endogenous interaction of DISC1with APP in neurons may be transient. The authors conclude that APP temporarily interacts with DISC1, leading to DISC1 translocation to the centrosome, where it regulates neuronal migration. Perhaps the disruption of a brief meeting of molecules sets the fate for the bearer, which is undetected until 20 years (schizophrenia) or 80 years (Alzheimer’s) later.

T. L. Young-Pearse et al., Biochemical and functional interaction of disrupted-in-schizophrenia 1 and amyloid precursor protein regulates neuronal migration during mammalian cortical development. J. Neurosci. 30, 10431–10440 (2010). [Abstract]

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