Expanded polyglutamines impair synaptic transmission and ubiquitin–proteasome system in Caenorhabditis elegans

Polyglutamine (polyQ) expansion in many proteins, including huntingtin and ataxin‐3, is pathogenic and responsible for neuronal dysfunction and degeneration. Although at least nine neurodegenerative diseases are caused by expanded polyQ, the pathogenesis of these diseases is still not well understood. In the present study, we used Caenorhabditis elegans to study the molecular mechanism of polyQ‐mediated toxicity. We expressed full‐length and truncated ataxin‐3 with different lengths of polyQ in the nervous system of C. elegans. We show that expanded polyQ interrupts synaptic transmission, and induces swelling and aberrant branching of neuronal processes. Using an ubiquitinated fluorescence reporter construct, we also showed that polyQ aggregates impair the ubiquitin–proteasome system in C. elegans. These results may provide information for further understanding the pathogenesis of polyQ diseases.

[1]  M. Labouesse.  [Caenorhabditis elegans]. , 2003, Medecine sciences : M/S.

[2]  N W Kowall,et al.  Proliferative and degenerative changes in striatal spiny neurons in Huntington's disease: a combined study using the section-Golgi method and calbindin D28k immunocytochemistry , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[3]  R. Rosenberg.  Machado‐Joseph disease: An autosomal dominant motor system degeneration , 1992, Movement disorders : official journal of the Movement Disorder Society.

[4]  Bin Zhang,et al.  Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[5]  C A Ross,et al.  Interference by Huntingtin and Atrophin-1 with CBP-Mediated Transcription Leading to Cellular Toxicity , 2001, Science.

[6]  F. Piccioni,et al.  Androgen receptor with elongated polyglutamine tract forms aggregates that alter axonal trafficking and mitochondrial distribution in motoneuronal processes , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  R. Kopito,et al.  Impairment of the ubiquitin-proteasome system by protein aggregation. , 2001, Science.

[8]  N. Munakata.  [Genetics of Caenorhabditis elegans]. , 1989, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[9]  E A Zemskov,et al.  Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. , 2001, Human molecular genetics.

[10]  S. Brenner,et al.  The structure of the nervous system of the nematode Caenorhabditis elegans. , 1986, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[11]  P. Armati,et al.  Oxidative stress induces axonal beading in cultured human brain tissue , 2003, Neurobiology of Disease.

[12]  N. Nukina,et al.  Impaired degradation of PKCalpha by proteasome in a cellular model of Huntington's disease. , 2003, Neuroreport.

[13]  Andreas Matouschek,et al.  Inefficient degradation of truncated polyglutamine proteins by the proteasome , 2004, The EMBO journal.

[14]  G. J. Harry,et al.  Acrylamide-induced alterations in axonal transport , 2007, Molecular Neurobiology.

[15]  I. Kanazawa,et al.  Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B. , 2000, Human molecular genetics.

[16]  Barrington G. Burnett,et al.  The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. , 2003, Human molecular genetics.

[17]  Scott T. Brady,et al.  Neuropathogenic Forms of Huntingtin and Androgen Receptor Inhibit Fast Axonal Transport , 2003, Neuron.

[18]  Í. Lopes-Cendes,et al.  Correlation between CAG repeat length and clinical features in Machado-Joseph disease. , 1995, American journal of human genetics.

[19]  N. Nukina,et al.  Increased expression of p62 in expanded polyglutamine‐expressing cells and its association with polyglutamine inclusions , 2004, Journal of neurochemistry.

[20]  A. Hart,et al.  Caenorhabditis elegans as a model system for triplet repeat diseases. , 2004, Methods in molecular biology.

[21]  I. Kanazawa,et al.  Caspase activation during apoptotic cell death induced by expanded polyglutamine in N2a cells. , 1999, Neuroreport.

[22]  J Dausset,et al.  Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[23]  L. Brain.  The Nervous System , 1963, Nature.

[24]  C. Dobson,et al.  Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases , 2002, Nature.

[25]  Mark R. Segal,et al.  Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death , 2004, Nature.

[26]  Shigenobu Nakamura,et al.  CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1 , 1994, Nature Genetics.

[27]  H. Paulson,et al.  Protein fate in neurodegenerative proteinopathies: polyglutamine diseases join the (mis)fold. , 1999, American journal of human genetics.

[28]  M. Nonet,et al.  Synaptic function is impaired but not eliminated in C. elegans mutants lacking synaptotagmin , 1993, Cell.

[29]  Cori Bargmann,et al.  Three C. elegans Rac proteins and several alternative Rac regulators control axon guidance, cell migration and apoptotic cell phagocytosis. , 2001, Development.

[30]  O. Hansson,et al.  Altered striatal amino acid neurotransmitter release monitored using microdialysis in R6/1 Huntington transgenic mice , 2001, The European journal of neuroscience.

[31]  Richard G. Brusch,et al.  Disruption of Axonal Transport by Loss of Huntingtin or Expression of Pathogenic PolyQ Proteins in Drosophila , 2003, Neuron.

[32]  E. Bennett,et al.  Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation. , 2005, Molecular cell.

[33]  Ronald Wetzel,et al.  Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. , 2004, Molecular cell.

[34]  H. Zoghbi,et al.  Neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin-proteasome system impairment and inversely correlates with the degree of nuclear inclusion formation. , 2005, Human molecular genetics.

[35]  Hilla Peretz,et al.  Ju n 20 03 Schrödinger ’ s Cat : The rules of engagement , 2003 .

[36]  Christopher A Ross,et al.  Polyglutamine Pathogenesis Emergence of Unifying Mechanisms for Huntington's Disease and Related Disorders , 2002, Neuron.

[37]  Huda Y. Zoghbi,et al.  Diseases of Unstable Repeat Expansion: Mechanisms and Common Principles , 2005, Nature Reviews Genetics.

[38]  C. Ross,et al.  Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. , 2001, Human molecular genetics.