Presynaptic dysfunction in Huntington's disease.

HD (Huntington's disease) is produced by the expression of mutant forms of the protein htt (huntingtin) containing a pathologically expanded poly-glutamine repeat. For unknown reasons, in HD patients and HD mouse models, neurons from the striatum and cerebral cortex degenerate and lead to motor dysfunction and dementia. Synaptic transmission in those neurons becomes progressively altered during the course of the disease. However, the relationship between synaptic dysfunction and neurodegeneration in HD is not yet clear. Are there early specific functional synaptic changes preceding symptoms and neurodegeneration? What is the role of those changes in neuronal damage? Recent experiments in a Drosophila model of HD have showed that abnormally increased neurotransmitter release might be a leading cause of neurodegeneration. In the present review, we summarize recently described synaptic alterations in HD animal models and discuss potential underlying molecular mechanisms.

[1]  X. Chen,et al.  Neuroprotective Effects of Inositol 1,4,5-Trisphosphate Receptor C-Terminal Fragment in a Huntington's Disease Mouse Model , 2009, The Journal of Neuroscience.

[2]  P. Verstreken,et al.  Suppression of Neurodegeneration and Increased Neurotransmission Caused by Expanded Full-Length Huntingtin Accumulating in the Cytoplasm , 2008, Neuron.

[3]  S. W. Davies,et al.  Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice , 1996, Cell.

[4]  E. Isacoff,et al.  Drosophila Huntingtin-Interacting Protein 14 Is a Presynaptic Protein Required for Photoreceptor Synaptic Transmission and Expression of the Palmitoylated Proteins Synaptosome-Associated Protein 25 and Cysteine String Protein , 2007, The Journal of Neuroscience.

[5]  M. MacDonald,et al.  Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[6]  L. Raymond,et al.  Disruption of the endocytic protein HIP1 results in neurological deficits and decreased AMPA receptor trafficking , 2003, The EMBO journal.

[7]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[8]  P. Brundin,et al.  Depletion of rabphilin 3A in a transgenic mouse model (R6/1) of Huntington's disease, a possible culprit in synaptic dysfunction , 2005, Neurobiology of Disease.

[9]  Carlos Cepeda,et al.  Increased GABAergic function in mouse models of Huntington's disease: Reversal by BDNF , 2004, Journal of neuroscience research.

[10]  Patrik Brundin,et al.  Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment , 2009, Proceedings of the National Academy of Sciences.

[11]  R. Llinás,et al.  Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[12]  P. Brundin,et al.  Synaptic dysfunction in Huntington’s disease: a new perspective , 2005, Cellular and Molecular Life Sciences CMLS.

[13]  M. Hayden,et al.  Huntingtin and Huntingtin-Associated Protein 1 Influence Neuronal Calcium Signaling Mediated by Inositol-(1,4,5) Triphosphate Receptor Type 1 , 2003, Neuron.

[14]  Chun-Fang Huang,et al.  Pathogenic Huntingtin Inhibits Fast Axonal Transport by Activating JNK3 and Phosphorylating Kinesin , 2009, Nature Neuroscience.

[15]  P. Verstreken,et al.  Huntingtin-interacting protein 14, a palmitoyl transferase required for exocytosis and targeting of CSP to synaptic vesicles , 2007, The Journal of cell biology.

[16]  Claire-Anne Gutekunst,et al.  Huntingtin-Interacting Protein HIP14 Is a Palmitoyl Transferase Involved in Palmitoylation and Trafficking of Multiple Neuronal Proteins , 2004, Neuron.

[17]  J. Lucas,et al.  Full Motor Recovery Despite Striatal Neuron Loss and Formation of Irreversible Amyloid-Like Inclusions in a Conditional Mouse Model of Huntington's Disease , 2005, The Journal of Neuroscience.

[18]  Fabrice P Cordelières,et al.  Huntingtin Controls Neurotrophic Support and Survival of Neurons by Enhancing BDNF Vesicular Transport along Microtubules , 2004, Cell.

[19]  P. Muchowski,et al.  Cysteine String Protein (CSP) Inhibition of N-type Calcium Channels Is Blocked by Mutant Huntingtin* , 2003, Journal of Biological Chemistry.

[20]  I. Bezprozvanny,et al.  HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5‐trisphosphate‐induced Ca2+ release in primary culture of striatal medium spiny neurons , 2004, The European journal of neuroscience.

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

[22]  Shahid Hameed,et al.  Crosstalk between huntingtin and syntaxin 1A regulates N-type calcium channels , 2005, Molecular and Cellular Neuroscience.

[23]  Thomas C. Südhof,et al.  α-Synuclein Cooperates with CSPα in Preventing Neurodegeneration , 2005, Cell.

[24]  Michael A. Mancini,et al.  Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1 , 1998, Nature Genetics.

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

[26]  J. Roder,et al.  Huntingtin-Interacting Protein 1 Influences Worm and Mouse Presynaptic Function and Protects Caenorhabditis elegans Neurons against Mutant Polyglutamine Toxicity , 2007, The Journal of Neuroscience.

[27]  R. Ferrante,et al.  SCAMP5 Links Endoplasmic Reticulum Stress to the Accumulation of Expanded Polyglutamine Protein Aggregates via Endocytosis Inhibition* , 2009, Journal of Biological Chemistry.

[28]  Dimitri Krainc,et al.  Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease , 2002, Science.

[29]  R. Ferrante,et al.  Mouse models of Huntington's disease and methodological considerations for therapeutic trials. , 2009, Biochimica et biophysica acta.

[30]  Impaired ubiquitin–proteasome system activity in the synapses of Huntington's disease mice , 2008 .

[31]  Vijay H Shah,et al.  Mutant huntingtin inhibits clathrin-independent endocytosis and causes accumulation of cholesterol in vitro and in vivo. , 2006, Human molecular genetics.

[32]  T. Südhof,et al.  Rabphilin regulates SNARE‐dependent re‐priming of synaptic vesicles for fusion , 2006, The EMBO journal.

[33]  J. A. Parker,et al.  Genetic and pharmacological suppression of polyglutamine-dependent neuronal dysfunction in Caenorhabditis elegans , 2007, Journal of Molecular Neuroscience.

[34]  Alexander Varshavsky,et al.  The ubiquitin system. , 1998, Annual review of biochemistry.

[35]  L. Raymond,et al.  Increased Sensitivity to N-Methyl-D-Aspartate Receptor-Mediated Excitotoxicity in a Mouse Model of Huntington's Disease , 2002, Neuron.

[36]  J. Lucas,et al.  Is the ubiquitin-proteasome system impaired in Huntington’s disease? , 2007, Cellular and Molecular Life Sciences.

[37]  T. Südhof,et al.  The Synaptic Vesicle Protein CSPα Prevents Presynaptic Degeneration , 2004, Neuron.

[38]  Carlos Cepeda,et al.  Alterations in Cortical Excitation and Inhibition in Genetic Mouse Models of Huntington's Disease , 2009, The Journal of Neuroscience.

[39]  Patrik Brundin,et al.  Loss of SNAP‐25 and rabphilin 3a in sensory‐motor cortex in Huntington’s disease , 2007, Journal of neurochemistry.

[40]  Beatriz Alvarez-Castelao,et al.  Inhibition of 26S proteasome activity by huntingtin filaments but not inclusion bodies isolated from mouse and human brain , 2006, Journal of neurochemistry.

[41]  T. Südhof,et al.  Novel SCAMPs Lacking NPF Repeats: Ubiquitous and Synaptic Vesicle-Specific Forms Implicate SCAMPs in Multiple Membrane-Trafficking Functions , 2000, The Journal of Neuroscience.

[42]  Casey Cook,et al.  The Ubiquitin-Proteasome Reporter GFPu Does Not Accumulate in Neurons of the R6/2 Transgenic Mouse Model of Huntington's Disease , 2009, PloS one.

[43]  S. Pulst,et al.  Proteasome Inhibition Triggers Activity-Dependent Increase in the Size of the Recycling Vesicle Pool in Cultured Hippocampal Neurons , 2006, The Journal of Neuroscience.

[44]  Iris Salecker,et al.  Polyglutamine-Expanded Human Huntingtin Transgenes Induce Degeneration of Drosophila Photoreceptor Neurons , 1998, Neuron.

[45]  Howard Schulman,et al.  Global changes to the ubiquitin system in Huntington's disease , 2007, Nature.

[46]  Carlos Cepeda,et al.  Transient and Progressive Electrophysiological Alterations in the Corticostriatal Pathway in a Mouse Model of Huntington's Disease , 2003, The Journal of Neuroscience.

[47]  J. Littleton,et al.  Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[48]  J. Lucas,et al.  Altered P2X7‐receptor level and function in mouse models of Huntington's disease and therapeutic efficacy of antagonist administration , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[49]  J. Kaplan,et al.  Factors regulating the abundance and localization of synaptobrevin in the plasma membrane. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Isidro Ferrer,et al.  Biochemical, Ultrastructural, and Reversibility Studies on Huntingtin Filaments Isolated from Mouse and Human Brain , 2004, The Journal of Neuroscience.