ALBERT

Description: Machado-Joseph disease (MJD; also called spinocerebellar ataxia type 3) is a dominantly inherited late-onset neurodegenerative disorder caused by expansion of polyglutamine (polyQ)-encoding CAG repeats in the MJD1 gene (also known as ATXN3). Proteolytic liberation of highly aggregation-prone polyQ fragments from the protective sequence of the MJD1 gene product ataxin 3 (ATXN3) has been proposed to trigger the formation of ATXN3-containing aggregates, the neuropathological hallmark of MJD. ATXN3 fragments are detected in brain tissue of MJD patients and transgenic mice expressing mutant human ATXN3(Q71), and their amount increases with disease severity, supporting a relationship between ATXN3 processing and disease progression. The formation of early aggregation intermediates is thought to have a critical role in disease initiation, but the precise pathogenic mechanism operating in MJD has remained elusive. Here we show that L-glutamate-induced excitation of patient-specific induced pluripotent stem cell (iPSC)-derived neurons initiates Ca(2+)-dependent proteolysis of ATXN3 followed by the formation of SDS-insoluble aggregates. This phenotype could be abolished by calpain inhibition, confirming a key role of this protease in ATXN3 aggregation. Aggregate formation was further dependent on functional Na(+) and K(+) channels as well as ionotropic and voltage-gated Ca(2+) channels, and was not observed in iPSCs, fibroblasts or glia, thereby providing an explanation for the neuron-specific phenotype of this disease. Our data illustrate that iPSCs enable the study of aberrant protein processing associated with late-onset neurodegenerative disorders in patient-specific neurons.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Koch, Philipp -- Breuer, Peter -- Peitz, Michael -- Jungverdorben, Johannes -- Kesavan, Jaideep -- Poppe, Daniel -- Doerr, Jonas -- Ladewig, Julia -- Mertens, Jerome -- Tuting, Thomas -- Hoffmann, Per -- Klockgether, Thomas -- Evert, Bernd O -- Wullner, Ullrich -- Brustle, Oliver -- England -- Nature. 2011 Nov 23;480(7378):543-6. doi: 10.1038/nature10671.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn and Hertie Foundation, 53127 Bonn, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22113611" target="_blank"〉PubMed〈/a〉

Description: Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742055/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742055/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mertens, Jerome -- Wang, Qiu-Wen -- Kim, Yongsung -- Yu, Diana X -- Pham, Son -- Yang, Bo -- Zheng, Yi -- Diffenderfer, Kenneth E -- Zhang, Jian -- Soltani, Sheila -- Eames, Tameji -- Schafer, Simon T -- Boyer, Leah -- Marchetto, Maria C -- Nurnberger, John I -- Calabrese, Joseph R -- Odegaard, Ketil J -- McCarthy, Michael J -- Zandi, Peter P -- Alda, Martin -- Nievergelt, Caroline M -- Pharmacogenomics of Bipolar Disorder Study -- Mi, Shuangli -- Brennand, Kristen J -- Kelsoe, John R -- Gage, Fred H -- Yao, Jun -- MH106056/MH/NIMH NIH HHS/ -- R01 MH106056/MH/NIMH NIH HHS/ -- U01 MH092758/MH/NIMH NIH HHS/ -- U01 MH92758/MH/NIMH NIH HHS/ -- England -- Nature. 2015 Nov 5;527(7576):95-9. doi: 10.1038/nature15526. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, McGovern Institute for Brain Research, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; The Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, California 92037, USA. ; The Salk Institute for Biological Studies, Stem Cell Core, La Jolla, California 92037, USA. ; Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China. ; Department of Psychiatry, Indiana University, Indianapolis, Indiana 46202, USA. ; Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio 44106, USA. ; Department of Psychiatry, University of Bergen, Bergen 5020, Norway. ; Department of Psychiatry, VA San Diego Healthcare System, La Jolla, California 92151, USA. ; Department of Psychiatry, University of California San Diego, La Jolla, California, 92093, USA. ; Department of Psychiatry, Johns Hopkins University, Baltimore, Maryland 21218, USA. ; Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, B3H2E2, Canada. ; Department of Psychiatry, Mount Sinai School of Medicine, New York, New York 10029, USA. ; Jiangsu Collaborative Innovation Center for Language Ability, Jiangsu Normal University, Xuzhou 221009, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524527" target="_blank"〉PubMed〈/a〉