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      Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS

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          Abstract

          Amyotrophic lateral sclerosis (ALS) is a devastating human neurodegenerative disease. The causes of ALS are poorly understood, although the protein TDP-43 has been suggested to play a critical role in disease pathogenesis. Here we show that Ataxin-2, a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2 (SCA2), is a potent modifier of TDP-43 toxicity in animal and cellular models. The proteins associate in a complex that depends on RNA. Ataxin-2 is abnormally localized in spinal cord neurons of ALS patients. Likewise, TDP-43 shows mislocalization in SCA2. To assess a role in ALS, we analyzed the Ataxin-2 gene ( ATXN2) in 915 ALS patients. We found intermediate-length polyQ expansions (27–33 Qs) in ATXN2 significantly associated with ALS. These data establish ATXN2 as a relatively common ALS disease susceptibility gene. Further, these findings indicate that the TDP-43/Ataxin-2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.

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          Most cited references 30

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          Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

          Ubiquitin-positive, tau- and alpha-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.
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            Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models.

            Alpha-synuclein (alphaSyn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson's disease (PD). In yeast cells and in neurons alphaSyn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following alphaSyn expression in yeast was a block in endoplasmic reticulum (ER)-to-Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphatase Ypt1p, which associated with cytoplasmic alphaSyn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against alphaSyn-induced dopaminergic neuron loss in animal models of PD. Thus, synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.
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              Trinucleotide repeat disorders.

               Huda Zoghbi,  Mark Orr (2006)
              The discovery that expansion of unstable repeats can cause a variety of neurological disorders has changed the landscape of disease-oriented research for several forms of mental retardation, Huntington disease, inherited ataxias, and muscular dystrophy. The dynamic nature of these mutations provided an explanation for the variable phenotype expressivity within a family. Beyond diagnosis and genetic counseling, the benefits from studying these disorders have been noted in both neurobiology and cell biology. Examples include insight about the role of translational control in synaptic plasticity, the role of RNA processing in the integrity of muscle and neuronal function, the importance of Fe-S-containing enzymes for cellular energy, and the dramatic effects of altering protein conformations on neuronal function and survival. It is exciting that within a span of 15 years, pathogenesis studies of this class of disorders are beginning to reveal pathways that are potential therapeutic targets.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                0028-0836
                1476-4687
                1 October 2010
                26 August 2010
                1 February 2011
                : 466
                : 7310
                : 1069-1075
                Affiliations
                [1 ] Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia PA, 19104
                [2 ] Department of Biology, the Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia PA, 19104
                [3 ] Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia PA, 19104
                [4 ] Department of Neurology, University of Pennsylvania, Philadelphia PA, 19104
                [5 ] The Children’s Hospital of Philadelphia, Philadelphia, PA 19104
                [6 ] Institute of Clinical Neuroanatomy, Dr. Senckenberg Anatomy, Goethe University, Frankfurt am Main, Germany
                [7 ] Molecular Neurogenetics, Department of Neurology, Goethe University, Frankfurt am Main, Germany
                Author notes
                [9 ]Correspondence should be addressed to: A.D.G. or N.M.B. Aaron D. Gitler, 1109 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104, 215-573-8251 (phone), 215-898-9871 (fax), gitler@ 123456mail.med.upenn.edu . Nancy M. Bonini, 306 Leidy Labs, Philadelphia, PA 19104, 215-573-9267 (phone), 215-573-5754 (fax), nbonini@ 123456sas.upenn.edu
                [8]

                These authors contributed equally.

                Article
                nihpa217752
                10.1038/nature09320
                2965417
                20740007

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                Funding
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: Office of the Director : NIH
                Award ID: R01 NS065317-03 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: Office of the Director : NIH
                Award ID: R01 NS065317-02 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: Office of the Director : NIH
                Award ID: R01 NS065317-01 ||NS
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Funded by: Office of the Director : NIH
                Award ID: DP2 OD004417-01 ||OD
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