NMDA and AMPA-type glutamate receptors and their bound membrane-associated guanylate kinases (MAGUKs) are critical for synapse development and plasticity. We hypothesised that these proteins may play a role in the changes in synapse function that occur in Huntington’s disease (HD) and Parkinson’s disease (PD). We performed immunohistochemical analysis of human postmortem brain tissue to examine changes in the expression of SAP97, PSD-95, GluA2 and GluN1 in human control, and HD- and PD-affected hippocampus and striatum. Significant increases in SAP97 and PSD-95 were observed in the HD and PD hippocampus, and PSD95 was downregulated in HD striatum. We observed a significant increase in GluN1 in the HD hippocampus and a decrease in GluA2 in HD and PD striatum. Parallel immunohistochemistry experiments in the YAC128 mouse model of HD showed no change in the expression levels of these synaptic proteins. Our human data show that major but different changes occur in glutamatergic proteins in HD versus PD human brains. Moreover, the changes in human HD brains differ from those occurring in the YAC128 HD mouse model, suggesting that unique changes occur at a subcellular level in the HD human hippocampus. 1. Introduction Huntington’s disease (HD) and Parkinson’s disease (PD) are distinct neurodegenerative diseases that present with unique motor and cognitive symptoms. HD is an autosomal dominant inherited disease caused by the expansion of a polyglutamine repeat sequence in the huntingtin gene, which results in a progressive loss of medium spiny neurons in the striatum [1]. PD is a sporadic neurodegenerative disease, although there are rare familial cases. It is marked by the loss of dopaminergic neurons of the substantia nigra pars compacta, which leads to abnormal basal ganglia circuitry, resulting in motor symptoms [2, 3]. Treatments for these diseases are symptomatic and new therapeutic targets are of the essence. Emphasis is now being placed on the changes that occur at the synapse and the processes that underlie cognitive dysfunction as it has been shown that synaptic and cognitive dysfunction occurs long before the onset of clinical symptoms in the human [4–7]. Glutamate receptors are currently viewed as valuable therapeutic targets in both HD [6] and PD [7]. N-Methyl-D-Aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors and their bound postsynaptic density-membrane associated guanylate kinases (PSD-MAGUKs) are critical for synapse development and plasticity [8–12]. MAGUKs act as scaffolding
References
[1]
J. P. Vonsattel, R. H. Myers, T. J. Stevens, R. J. Ferrante, E. D. Bird, and E. P. Richardson Jr., “Neuropathological classification of Huntington's disease,” Journal of Neuropathology and Experimental Neurology, vol. 44, no. 6, pp. 559–577, 1985.
[2]
H. Braak, K. Del Tredici, U. Rüb, R. A. I. de Vos, E. N. H. Jansen Steur, and E. Braak, “Staging of brain pathology related to sporadic Parkinson's disease,” Neurobiology of Aging, vol. 24, no. 2, pp. 197–211, 2003.
[3]
W. R. G. Gibb, “Neuropathology of the substantia nigra,” European Neurology, vol. 31, no. 1, pp. 48–59, 1991.
[4]
J. S. Paulsen, D. R. Langbehn, J. C. Stout et al., “Detection of Huntington's disease decades before diagnosis: the Predict-HD study,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 79, no. 8, pp. 874–880, 2008.
[5]
S. Schippling, S. A. Schneider, K. P. Bhatia et al., “Abnormal motor cortex excitability in preclinical and very early Huntington's disease,” Biological Psychiatry, vol. 65, no. 11, pp. 959–965, 2009.
[6]
A. J. Milnerwood and L. A. Raymond, “Early synaptic pathophysiology in neurodegeneration: insights from Huntington's disease,” Trends in Neurosciences, vol. 33, no. 11, pp. 513–523, 2010.
[7]
K. A. Johnson, P. J. Conn, and C. M. Niswender, “Glutamate receptors as therapeutic targets for Parkinson's disease,” CNS and Neurological Disorders, vol. 8, no. 6, pp. 475–491, 2009.
[8]
J. M. Montgomery, P. L. Zamorano, and C. C. Garner, “MAGUKs in synapse assembly and function: an emerging view,” Cellular and Molecular Life Sciences, vol. 61, no. 7-8, pp. 911–929, 2004.
[9]
G. M. Elias, L. Funke, V. Stein, S. G. Grant, D. S. Bredt, and R. A. Nicoll, “Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins,” Neuron, vol. 52, no. 2, pp. 307–320, 2006.
[10]
D. Li, C. G. Specht, C. L. Waites et al., “SAP97 directs NMDA receptor spine targeting and synaptic plasticity,” Journal of Physiology, vol. 589, no. 18, pp. 4491–4510, 2011.
[11]
C. Zheng, G. K. Seabold, M. Horak, and R. S. Petralia, “MAGUKs, synaptic development, and synaptic plasticity,” Neuroscientist, vol. 17, no. 5, pp. 493–512, 2011.
[12]
C. Oliva, P. Escobedo, C. Astorga, C. Molina, and J. Sierralta, “Role of the maguk protein family in synapse formation and function,” Developmental Neurobiology, vol. 72, no. 1, pp. 57–72, 2012.
[13]
E. Schnell, M. Sizemore, S. Karimzadegan, L. Chen, D. S. Bredt, and R. A. Nicoll, “Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 21, pp. 13902–13907, 2002.
[14]
H.-C. Kornau, L. T. Schenker, M. B. Kennedy, and P. H. Seeburg, “Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95,” Science, vol. 269, no. 5231, pp. 1737–1740, 1995.
[15]
M. Niethammer, E. Kim, and M. Sheng, “Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases,” The Journal of Neuroscience, vol. 16, no. 7, pp. 2157–2163, 1996.
[16]
A. S. Leonard, M. A. Davare, M. C. Horne, C. C. Garner, and J. W. Hell, “SAP97 is associated with the α-amino-3-hydroxy-5-methylisoxazole-4- propionic acid receptor GluR1 subunit,” The Journal of Biological Chemistry, vol. 273, no. 31, pp. 19518–19524, 1998.
[17]
P. Bassand, A. Bernard, A. Rafiki, D. Gayet, and M. Khrestchatisky, “Differential interaction of the tSXV motifs of the NR1 and NR2A NMDA receptor subunits with PSD-95 and SAP97,” European Journal of Neuroscience, vol. 11, no. 6, pp. 2031–2043, 1999.
[18]
O. Jeyifous, C. L. Waites, C. G. Specht et al., “SAP97 and CASK mediate sorting of NMDA receptors through a previously unknown secretory pathway,” Nature Neuroscience, vol. 12, no. 8, pp. 1011–1019, 2009.
[19]
F. Gardoni, B. Picconi, V. Ghiglieri et al., “A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia,” The Journal of Neuroscience, vol. 26, no. 11, pp. 2914–2922, 2006.
[20]
F. Gardoni, V. Ghiglieri, M. D. Luca, and P. Calabresi, “Assemblies of glutamate receptor subunits with post-synaptic density proteins and their alterations in Parkinson's disease,” Progress in Brain Research, vol. 183, pp. 169–182, 2010.
[21]
Y. Sun, A. Savanenin, P. H. Reddy, and Y. F. Liu, “Polyglutamine-expanded Huntingtin promotes sensitization of N-methyl-D-aspartate receptors via post-synaptic density 95,” The Journal of Biological Chemistry, vol. 276, no. 27, pp. 24713–24718, 2001.
[22]
M. M. Zeron, O. Hansson, N. Chen et al., “Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease,” Neuron, vol. 33, no. 6, pp. 849–860, 2002.
[23]
J. Shehadeh, H. B. Fernandes, M. M. Z. Mullins et al., “Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease,” Neurobiology of Disease, vol. 21, no. 2, pp. 392–403, 2006.
[24]
M. M. Y. Fan, H. B. Fernandes, L. Y. J. Zhang, M. R. Hayden, and L. A. Raymond, “Altered NMDA receptor trafficking in a yeast artificial chromosome transgenic mouse model of Huntington's disease,” The Journal of Neuroscience, vol. 27, no. 14, pp. 3768–3779, 2007.
[25]
J. Fan, C. M. Cowan, L. Y. J. Zhang, M. R. Hayden, and L. A. Raymond, “Interaction of postsynaptic density protein-95 with NMDA receptors influences excitotoxicity in the yeast artificial chromosome mouse model of Huntington's disease,” The Journal of Neuroscience, vol. 29, no. 35, pp. 10928–10938, 2009.
[26]
J. Fan, C. M. Gladding, L. Wang et al., “P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease,” Neurobiology of Disease, vol. 45, no. 3, pp. 999–1009, 2012.
[27]
J. F. Torres-Peraza, A. Giralt, J. M. García-Martínez, E. Pedrosa, J. M. Canals, and J. Alberch, “Disruption of striatal glutamatergic transmission induced by mutant huntingtin involves remodeling of both postsynaptic density and NMDA receptor signaling,” Neurobiology of Disease, vol. 29, no. 3, pp. 409–421, 2008.
[28]
B. R. Jarabek, R. P. Yasuda, and B. B. Wolfe, “Regulation of proteins affecting NMDA receptor-induced excitotoxicity in a Huntington's mouse model,” Brain, vol. 127, no. 3, pp. 505–516, 2004.
[29]
J. E. Nash, T. H. Johnston, G. L. Collingridge, C. C. Garner, and J. M. Brotchie, “Subcellular redistribution of the synapse-associated proteins PSD-95 and SAP97 in animal models of Parkinson's disease and L-DOPA-induced dyskinesia,” The FASEB Journal, vol. 19, no. 6, pp. 583–585, 2005.
[30]
M. M. Y. Fan and L. A. Raymond, “N-methyl-d-aspartate (NMDA) receptor function and excitotoxicity in Huntington's disease,” Progress in Neurobiology, vol. 81, no. 5-6, pp. 272–293, 2007.
[31]
C. L. Waites, C. G. Specht, K. Hartel et al., “Synaptic SAP97 isoforms regulate AMPA receptor dynamics and access to presynaptic glutamate,” The Journal of Neuroscience, vol. 29, no. 14, pp. 4332–4345, 2009.
[32]
H. J. Waldvogel, K. Baer, K. L. Allen, M. I. Rees, and R. L. M. Faull, “Glycine receptors in the striatum, globus pallidus, and substantia nigra of the human brain: an immunohistochemical study,” Journal of Comparative Neurology, vol. 502, no. 6, pp. 1012–1029, 2007.
[33]
H. J. Waldvogel, M. A. Curtis, K. Baer, M. I. Rees, and R. L. M. Faull, “Immunohistochemical staining of post-mortem adult human brain sections,” Nature Protocols, vol. 1, no. 6, pp. 2719–2732, 2007.
[34]
G. Leuba, A. Savioz, A. Vernay et al., “Differential changes in synaptic proteins in the Alzheimer frontal cortex with marked increase in PSD-95 postsynaptic protein,” Journal of Alzheimer's Disease, vol. 15, no. 1, pp. 139–151, 2008.
[35]
I. Romero-Calvo, B. Ocón, P. Martínez-Moya et al., “Reversible Ponceau staining as a loading control alternative to actin in Western blots,” Analytical Biochemistry, vol. 401, no. 2, pp. 318–320, 2010.
[36]
N. Sans, C. Racca, R. S. Petralia, Y. Wang, J. McCallum, and R. J. Wenthold, “Synapse-associated protein 97 selectively associates with a subset of AMPA receptors early in their biosynthetic pathway,” The Journal of Neuroscience, vol. 21, no. 19, pp. 7506–7516, 2001.
[37]
R. J. Wenthold and K. W. Roche, “The organization and regulation of non-NMDA receptors in neurons,” Progress in Brain Research, vol. 116, pp. 133–152, 1998.
[38]
A. D. Lawrence, J. R. Hodges, A. E. Rosser et al., “Evidence for specific cognitive deficits in preclinical Huntington's disease,” Brain, vol. 121, no. 7, pp. 1329–1341, 1998.
[39]
A. Montoya, B. H. Price, M. Menear, and M. Lepage, “Brain imaging and cognitive dysfunctions in Huntington's disease,” Journal of Psychiatry and Neuroscience, vol. 31, no. 1, pp. 21–29, 2006.
[40]
A. Giralt, M. Puigdellívol, O. Carretón et al., “Long-term memory deficits in Huntington's disease are associated with reduced CBP histone acetylase activity,” Human Molecular Genetics, vol. 21, no. 6, pp. 1203–1216, 2012.
[41]
J. M. Van Raamsdonk, Z. Murphy, E. J. Slow, B. R. Leavitt, and M. R. Hayden, “Selective degeneration and nuclear localization of mutant huntingtin in the YAC128 mouse model of Huntington disease,” Human Molecular Genetics, vol. 14, no. 24, pp. 3823–3835, 2005.
[42]
J. B. Carroll, J. P. Lerch, S. Franciosi et al., “Natural history of disease in the YAC128 mouse reveals a discrete signature of pathology in Huntington disease,” Neurobiology of Disease, vol. 43, no. 1, pp. 257–265, 2011.
[43]
J. M. Van Raamsdonk, J. Pearson, D. A. Rogers et al., “Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease,” Human Molecular Genetics, vol. 14, no. 10, pp. 1379–1392, 2005.
[44]
J. M. Van Raamsdonk, J. Pearson, D. A. Rogers et al., “Ethyl-EPA treatment improves motor dysfunction, but not neurodegeneration in the YAC128 mouse model of Huntington disease,” Experimental Neurology, vol. 196, no. 2, pp. 266–272, 2005.
[45]
J. M. Van Raamsdonk, J. Pearson, Z. Murphy, M. R. Hayden, and B. R. Leavitt, “Wild-type huntingtin ameliorates striatal neuronal atrophy but does not prevent other abnormalities in the YAC128 mouse model of Huntington disease,” BMC Neuroscience, vol. 7, article 80, 2006.
[46]
R. Diamond, R. F. White, R. H. Myers et al., “Evidence of presymptomatic cognitive decline in Huntington's disease,” Journal of Clinical and Experimental Neuropsychology, vol. 14, no. 6, pp. 961–975, 1992.
[47]
T. Ziemssen and H. Reichmann, “Non-motor dysfunction in Parkinson's disease,” Parkinsonism and Related Disorders, vol. 13, no. 6, pp. 323–332, 2007.
[48]
H. Cui, A. Hayashi, H. Sun et al., “PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors,” The Journal of Neuroscience, vol. 27, no. 37, pp. 9901–9915, 2007.
[49]
G. A. Graveland, R. S. Williams, and M. DiFiglia, “Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease,” Science, vol. 227, no. 4688, pp. 770–773, 1985.
[50]
G. J. Klapstein, R. S. Fisher, H. Zanjani et al., “Electrophysiological and morphological changes in striatal spiny neurons in R6/2 Huntington's disease transgenic mice,” Journal of Neurophysiology, vol. 86, no. 6, pp. 2667–2677, 2001.
[51]
T. L. Spires, H. E. Grote, S. Garry et al., “Dendritic spine pathology and deficits in experience-dependent dendritic plasticity in R6/1 Huntington's disease transgenic mice,” European Journal of Neuroscience, vol. 19, no. 10, pp. 2799–2807, 2004.
[52]
A. B. Young, J. T. Greenamyre, Z. Hollingworth et al., “NMDA receptor losses in putamen from patients with Huntington's disease,” Science, vol. 241, no. 4868, pp. 981–983, 1988.
[53]
G. E. Hardingham, Y. Fukunaga, and H. Bading, “Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways,” Nature Neuroscience, vol. 5, no. 5, pp. 405–414, 2002.
[54]
S. Okamoto, M. A. Pouladi, M. Talantova et al., “Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin,” Nature Medicine, vol. 15, no. 12, pp. 1407–1413, 2009.
[55]
A. J. Milnerwood, C. M. Gladding, M. A. Pouladi et al., “Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice,” Neuron, vol. 65, no. 2, pp. 178–190, 2010.
[56]
K. L. Double, V. N. Dedov, H. Fedorow et al., “The comparative biology of neuromelanin and lipofuscin in the human brain,” Cellular and Molecular Life Sciences, vol. 65, no. 11, pp. 1669–1682, 2008.
[57]
J. G. Hodgson, N. Agopyan, C. Gutekunst et al., “A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration,” Neuron, vol. 23, no. 1, pp. 181–192, 1999.
[58]
K. P. S. J. Murphy, R. J. Carter, L. A. Lione et al., “Abnormal synaptic plasticity and impaired spatial cognition in mice transgenic for exon 1 of the human Huntington's disease mutation,” The Journal of Neuroscience, vol. 20, no. 13, pp. 5115–5123, 2000.
[59]
M. T. Usdin, P. F. Shelbourne, R. M. Myers, and D. V. Madison, “Impaired synaptic plasticity in mice carrying the Huntington's disease mutation,” Human Molecular Genetics, vol. 8, no. 5, pp. 839–846, 1999.
[60]
G. Leuba, C. Walzer, A. Vernay et al., “Postsynaptic density protein PSD-95 expression in Alzheimer's disease and okadaic acid induced neuritic retraction,” Neurobiology of Disease, vol. 30, no. 3, pp. 408–419, 2008.
[61]
R. K. Graham, Y. Deng, E. J. Slow et al., “Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant Huntingtin,” Cell, vol. 125, no. 6, pp. 1179–1191, 2006.
[62]
I. Rattray, E. Smith, R. Gale, K. Matsumoto, G. P. Bates, and M. Modo, “Correlations of behavioral deficits with brain pathology assessed through longitudinal MRI and histopathology in the R6/2 mouse model of HD,” PLoS ONE, vol. 8, Article ID e60012, 2013.
[63]
J. M. Van Raamsdonk, J. Pearson, E. J. Slow, S. M. Hossain, B. R. Leavitt, and M. R. Hayden, “Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington's disease,” The Journal of Neuroscience, vol. 25, no. 16, pp. 4169–4180, 2005.
[64]
M. A. Pouladi, R. K. Graham, J. M. Karasinska et al., “Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin,” Brain, vol. 132, no. 4, pp. 919–932, 2009.
[65]
J. M. Simpson, J. Gil-Mohapel, M. A. Pouladi et al., “Altered adult hippocampal neurogenesis in the YAC128 transgenic mouse model of Huntington disease,” Neurobiology of Disease, vol. 41, no. 2, pp. 249–260, 2011.
[66]
J. Nithianantharajah, C. Barkus, M. Murphy, and A. J. Hannan, “Gene-environment interactions modulating cognitive function and molecular correlates of synaptic plasticity in Huntington's disease transgenic mice,” Neurobiology of Disease, vol. 29, no. 3, pp. 490–504, 2008.
[67]
A. W. Dunah, Y. Wang, R. P. Yasuda et al., “Alterations in subunit expression, composition, and phosphorylation of striatal N-methyl-D-aspartate glutamate receptors in a rat 6-hydroxydopamine model of Parkinson's disease,” Molecular Pharmacology, vol. 57, no. 2, pp. 342–352, 2000.
[68]
M. A. Ariano, N. Wagle, and A. E. Grissell, “Neuronal vulnerability in mouse models of Huntington's disease: membrane channel protein changes,” Journal of Neuroscience Research, vol. 80, no. 5, pp. 634–645, 2005.
[69]
C. Cepeda, M. A. Ariano, C. R. Calvert et al., “NMDA receptor function in mouse models of Huntington disease,” Journal of Neuroscience Research, vol. 66, no. 4, pp. 525–539, 2001.
