Nixon Laboratory
Levy Lab | |
Ohno Lab | |
Rao Lab | |
Head of Lab: Ralph Nixon, Ph.D., M.D.
The Fate of Pathogenic Proteins in Neurodegenerative Diseases
In major neurodegenerative diseases, such as
Alzheimer’s and Parkinson’s, the abnormal accumulation of one or more
polypeptides within or around neurons is central to pathogenesis. Our
research focuses on two aspects of neurobiology that govern the fate of
normal and pathogenic proteins: the regulation of proteolytic processing
and the control of protein export into axons and synapses. We have
identified dysfunction of the endosomal-lysosomal system, involving
altered endocytosis and mistrafficking of proteases to endosomes, as the
earliest known pathological response of neurons in Alzheimer’s disease.
Our cell modeling studies show early endosomes to be major generators of
the toxic ß-amyloid peptide and implicate dysfunction of endosomes in the
mechanism of ß-amyloid accumulation in "sporadic" Alzheimer’s, the most
common form of the disease. Genetic manipulations of proteolytic systems
in mice are being used, together with cell culture models, to determine
the consequences of endosomal-lysosomal and calpain system dysfunction on
processing of Alzheimer-related proteins, receptor-mediated signal
transduction, and neuronal cell death pathways.
To maintain neural circuitry, neurons transport a
large proportion of their newly synthesized proteins into axons. The
perikaryal accumulation of specific cytoskeletal proteins - a pathological
hallmark of Alzheimer’s, ALS, and other neurologic diseases - is believed
to arise in part from impaired axonal transport. A second interest of our
research is to identify the molecular determinants of cytoskeletal protein
transport and assembly in neurons. For example, we are defining the
minimum structural requirements for neurofilament translocation by
studying axonal transport and axon ultrastructure in mice after targeted
deletion or mutagenesis of each of the three neurofilament subunit genes.
Neurofilament transport is also regulated by sequential protein
phosphorylation, triggered in part by signals from oligodendroglial cells.
We have been determining the signaling pathways, phosphorylation sites,
and functional implications of these post-translational modifications.
Disease relevance is also being explored in several behavioral and
psychiatric settings.
Recent Publications
Original Reports
Mathews PM, Guerra CB, Jiang Y, Grbovic OM, Kao BH, Schmidt SD, Dinakar R, Mercken M, Hille-Rehfeld A, Rohrer J, Mehta P, Cataldo AM, Nixon RA. Alzheimer’s disease-related overexpression of the cation-dependent mannose 6-phosphate receptor increases Aß secretion: Role for altered lysosomal hydrolase distribution in ß-amyloidogenesis. J Biol Chem 2002; 277:5299-5307.
Yang D-S, Tandon A, Chen F, Yu G, Yu H, Arawaka S, Hasegawa H, Duthie M, Schmidt, SD, Triprayer V, Ramabhadran TV, Nixon RA, Mathews PM, Gandy SE, Mount HTJ, St. George-Hyslop P, Fraser PE. Mature Glycosylation and Trafficking of Nicastrin Modulate Its Binding to Presenilins. J Biol Chem 2002; 277:28135-28142.
Mathews PM, Jiang Y, Schmidt SD, Grbovic
Di Rosa G, Odrijin T, Nixon RA, Arancio O. Calpain inhibitors: a treatment for Alzheimer's disease. J Molec Neurosci. 2002 Aug-Oct;19(1-2):135-41..
Rozmahel R, Mount HT, Chen F, Nguyen V, Huang J, Erdebil S, Liauw J, Yu G, Hasegawa H, Gu Y, Song YQ, Schmidt SD, Nixon RA, Mathews PM, Bergeron C, Fraser P, Westaway D, St. George-Hyslop P. Alleles at the nicastrin locus modify presenilin 1-deficiency phenotype. Proc Nat Acad Sci USA 2002; 99:14452-14457.
Adamec E, Mohan PS, Vonsattel JP, Nixon RA. Calpain activation in neurodegenerative diseases: confocal immunofluorescence study with antibodies specifically recognizing the active form of calpain 2. Acta Neuropathologica 2002; 104:92-104.
Adamec E, Murrell JR, Takao M, Hobbs W, Nixon RA, Ghetti B, Vonsattel JP. P301L tauopathy: confocal immunofluorescence study of perinuclear aggregation of the mutated protein. J Neurol Sci 2002; 200:85-93.
Rao, MV, Engle LJ, Mohan PS, Yuan A, Qiu D, Cataldo A, Hassinger L,
Jacobsen S, Lee VM-Y, Andreadis A, Julien J-P, Bridgman PC, Nixon RA.
Rao MV, Garcia ML, Miyazaki Y, Gotow T, Yuan A, Mattina S, Ward CM, Calcutt NA, Uchiyama Y, Nixon RA, Cleveland DW. Gene replacement in mice reveals that the heavily phosphorylated tail of neurofilament heavy subunit does not affect axonal caliber or the transit of cargoes in slow axonal transport. J Cell Biol 2002; 158:681-693.
Noble W, Olm V, Takata K, Casey E, O M, Meyerson J, Gaynor K,
LaFrancois J, Wang L, Kondo T, Davies P, Burns M,
Battaglia F, Trinchese F, Liu S, Walter S, Nixon RA, Arancio O. Calpain inhibitors, a treatment for Alzheimer's disease: position paper. J Mol Neurosci. 2003 Jun;20(3):357-62.
Cataldo AM, Petanceska S, Peterhoff CM, Terio NB, Epstein CJ, Villar A, Carlson EJ, Staufenbiel M, and Nixon RA. Endosomal Abnormalities of Alzheimer’s Disease in a Trisomy 16 Mouse Model of Down Syndrome: Modulation by App Gene Dosage. J Neurosci. 2003; 23(17):6788-6792.
Grbovic OM, Mathews PM, Jiang Y, Schmidt SD, Dinaker R, Summers-Terio NB, Ceresa BP, Nixon RA, Cataldo AM. Rab5-stimulated up-regulation of the endocytic pathway increases intracellular ßCTF levels and A production. J Biol Chem. 2003; 278(33):31261-31268.
Yuan A, Rao MV, Kumar A, Julien J-P, Nixon RA. Neurofilament transport in vivo requires hetero-oligomer formation. J Neurosci. 2003; 23(28):9452-9458.
Phinney AL, Drisaldi B, Lugowski S, Schmidt SD, Coronado V, Liang Y, Horne P, Yang J, Sekoulidis J, Coomaraswamy J, Mathews PM, Nixon RA, Carlson GA, St George-Hyslop P, Westaway D. In vivo reduction of Aß by a mutant CuATPase7b transporter. Proc. Natl. Acad. Sci. USA. 2003; 100:14193-14198.
Rao MV, Campbell J, Yuan A, Kumar A, Gotow T, Uchiyama Y, Nixon RA. The neurofilament middle molecular weight subunit carboxyl terminal tail domains are essential for the radial growth and cytoskeletal architecture of axons but not for regulating neurofilament transport rate. J Cell Biol 2003; 163:1021-1031.
Pawlik M, Sastre M, Calero M, Mathews PM, Schmidt SD, Nixon RA, Levy E. Overexpression of human cystatin C in transgenic mice does not affect levels of endogenous brain amyloid ß peptide. J Molecular Neuroscience, 2004; 22 (1-2): 13-8.
Helpern JA, Lee S-P, Falangola MF, Dyakin VV, Bogart A, Estok K, Ardekani B, Duff K, Branch C, Wisniewski T, deLeon MJ, Wolf O, O’Shea J, Wegiel J, Nixon RA. Magnetic resonance imaging assessment of neuropathology in a transgenic mouse model of Alzheimer’s disease. Magn Reson Medicine, 2004; 51:794-798.
Laudon H, Mathews PM, Karlström H, Berman A, Farmery MR, Nixon RA, Winblad B, Gandy SE, Lendahl U, Lundkvist J, & Näslund J. Co-expressed presenilin 1 NTF and CTF form functional ß-secretase complexes in cells devoid of full-length protein. J Neurochem, 2004; 89:44-53.
Sadowski M, Pankiewicz J, Scholtzova H, Yong J, Quartermain D, Jensen CH, Duff K, Nixon RA, Gruen RJ, and Wisniewski T. Amyloid-ß deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice. JNEN, 2004; 63:418-428.
Yao J, Petanceska SS, Montine TJ, Holtzman DM, Schmidt SD, Parker SD, Callahan MJ, Lipinski WJ, Bisgaier CL, Turner BA, Nixon RA, Martins RN, Ouimet C, Smith JD, Ehrlich ME, Walker LC, Mathews PM, Gandy S. Aging, gender, and apoE isotype modulate parallel trends in levels of Alzheimer’s amyloid ß peptides and F2-isoprostane biomarkers. J. Neurochemistry 2004;90:1011-1018.
Cataldo AM, Petanceska S, Terio NB, Peterhoff CM, Durham R, Mercken M, Mehta PD, Buxbaum J, Haroutunian V, Nixon RA. Aß localization in abnormal endosomes: association with earliest Aß elevation in AD and Down syndrome. Neurobiol Aging 2004; 25:1263-1272.
Sastre M, Calero M, Pawlik M, Mathews PM, Kumar A, Danilov V, Schmidt SD, Nixon RA, Frangione B, and Levy E. Binding of cystatin C to Alzheimer’s amyloid-ß inhibits in vitro amyloid fibril formation. Neurobiol Aging 2004 25:1033-1043.
Yu WH, Kumar A, Peterhoff C, Shapiro Kulkane L, Uchiyama Y, Lamb BT, Cuervo AM, Nixon RA. Autophagic vacuoles are enriched in APP-secretase activities: Implications for Aß peptide over-production and localization in Alzheimer’s disease. Int J Biochem Cell Biol 2004; 36:2531-2540.
Lee S-P, Falangola MF, Nixon RA, Duff K, Helpern JA. Visualization of ß-Amyloid Plaques in a Transgenic Mouse Model of Alzheimer's disease using MR microscopy without contrast reagents. Magn Reson Med 2004; 52:538-544.
Cataldo AM, Peterhoff CM,
Carter TL, Verdile Giuseppe, Groth D, Bogush A, Thomas S, Shen P, Fraser PE, Mathews P, Nixon RA, Ehrlich ME, Kwok JB, St. George-Hyslop P, Schofield P, Li Y, Yang A, Martins RN, Gandy S. Alzheimer amyloid precursor aspartyl proteinase activity in CHAPSO homogenates of Spodoptera frugiperda cells. Alzheimer Dis Assoc Disord 2004; 18:261-263.
Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 2005; 64:113-122.
Falangola MF, Lee S-P, Nixon RA, Duff K, Helpern JA. Histological co-localization of iron in Aß plaques of PS/APP Transgenic Mice. Neurochem Res 2005; 30:201-205.
Mastrangelo P, Mathews PM, Chishti MA, Schmidt SD, Gu Y, Yang J, Mazella MJ, Coomaraswamy J, Horne P, Strome B, Pelly H, Levesque G, Eberling C, Jiang Y, Nixon RA, Rozmahel R, Fraser PE, St George-Hyslop P, Carlson GA, Westaway D. Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases. Proc Nat Acad Sci USA 2005; 102:8972-8977.
de Grey AD, Alvarez PJ, Brady RO, Cuervo AM, Jerome WG, McCarty PL, Nixon RA, Rittmann BE, Sparrow JR. Medical bioremediation: prospects for the application of microbial catabolic diversity to aging and several major age-related diseases. Ageing Res Rev 2005 4:315-338.
Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Naslund J, Mathews PM, Cataldo AM, Nixon RA. Macroautophagy– a novel amyloid-ß (Aß) peptide-generating pathway activated in Alzheimer’s disease. J Cell Biology 2005; 171:87-98.
Yuan A, Nixon RA, Rao MV. Deleting the phosphorylated tail domain of the neurofilament heavy subunit does not alter neurofilament transport rate in vivo. Neurosci Lett 2006; 393:264-268.
Liang J, Yin C, Doong H, Fang S, Peterhoff C, Nixon R, Monteiro MJ. Characterization of erasin (UBXD2): a new ER protein that promotes ER-associated protein degradation. J Cell Sci 2006; 119:4011-4024.
Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb, BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC. Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 2006; 51:29-42.
Yuan A, Rao MV, Sasaki T, Chen Y, Kumar A, Veeranna, Liem RK, Eyer J, Peterson AC, Julien JP, Nixon RA. Alpha-internexin is structurally and functionally associated with the neurofilament triplet proteins in the mature CNS. J Neurosci 2006; 26:10006-10019.
Boland B, Nixon RA. Neuronal macroautophagy : from development to degeneration. Mol Aspects Med 2006; 27:503-519.
Gandy S, Zhang YW, Ikin A, Schmidt SD, Levy E, Sheffield R, Nixon RA, Liao FF, Mathews PM, Xu H, Ehrlich ME. Alzheimer’s presenilin 1 modulates sorting of APP and its carboxyl-terminal fragments in cerebral neurons in vivo. J Neurochem 2007; 102:619-626.
Battaglia F, Wang HY, Ghilardi MF, Gashi E, Quartarone A, Friedman E, nixon RA. Cortical plasticity in Alzheimer’s disease in humans and rodents. Biol Psychiatry 2007; 62(12):1405-12.
Falangola MF, Dyakin VV, Lee SP, Bogart A, Babb JS, Duff K, Nixon R, Helpern JA. Quantitative MRI reveals aging-associated T2 changes in mouse models of Alzheimer’s disease. NMR Biomed 2007; 20:343-351.
Mi W, Pawlik M, Sastre M, Jung SS, Radvinsky DS, Klein AM, Sommer J, Schmidt SD, Nixon RA, Paul M. Mathews PM, Levy E. Cystatin C inhibits amyloid b deposition in Alzheimer’s disease mouse models. Nature Genet 2007; 39: 1440-1442.
Klionsky DJ, Abeliovich H, Agostinis P,…Nixon, RA… et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 2008; 4:151-175.
Yuan A, Kumar A, Peterhoff C, Duff K, Nixon RA. Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice. J Neurosci. 2008; 28:1682-1687.
Boland B, Kumar A, Lee S, Platt FM, Wegiel J, Yu WH, Nixon RA. Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer’s disease. J Neurosci 2008; 28:6926-6937. PMCID: PMC2676733
Azmitia EC and Nixon RA. Dystrophic serotonergic axons in neurodegenerative diseases. Brain Res. 2008; 1217C:185-194.
Trinchese F, Fa M, Liu S, Zhang H, Hidalgo A, Schmidt SD, Yamaguchi H, Yoshii N, Mathews PM, Nixon RA, Arancio O. Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease. J Clin Invest 2008; 118:2796-2807 PMC2441853.
Cataldo AM, Mathews PM, Boiteau AB, Hassinger LC, Peterhoff CM, Gruenberg J, Neve RL, Nixon RA. Down syndrome fibroblast model of Alzheimer-related endosome pathology: accelerated endocytosis promotes late endocytic defects. Am J Pathol 2008; 173:370-384 PMC2475775
Chen Y, Dyakin VV, Branch CA, Babak A, Yang D, Guilfoyle DN, Peterson J, Peterhoff C, Ginsberg SD, Cataldo AM, Nixon RA. In vivo MRI identifies specific cholinergic circuitry deficits in a mouse model of Down Syndrome. Neurobiol Aging 2008 (Epub ahead of print).
Yang DS, Kumar A, Stavrides P, Peterson J, Peterhoff CM, Pawlik M, Levy E, Cataldo AM, Nixon RA. Neuronal apoptosis and autophagy crosstalk in aging PS/APP mice, a model of Alzheimer’s disease. Am J Pathol 2008; 173:665-681. PMC2527090.
Rao MV, Mohan PS, Peterhoff, CM, Yang DS, Schmidt SD, Stavrides PH, Campbell J, Chen Y, Jiang Y, Paskevich PA, Cataldo AM, Haroutunian V, Nixon RA. Marked calpastatin (CAST) depletion in Alzheimer’s disease accelerates cytoskeleton disruption and neurodegeneration: Neuroprotection by CAST over-expression. J Neurosci 2008; 28:12241-54. PMCID: PMC Journal – In Process.
Veeranna, Lee JH, Pareek TK, Jaffee H, Boland B, Vinod KY, Amin N, Kulkarni AB, Pant HC, Nixon RA. Neurofilament tail phosphorylation: Identity of the RT-97 phosphoepitope and regulation in neurons by cross-talk among proline-directed kinases. J Neurochem 2008; 107:35-49. PMCID: PMC Journal – In Process.
Planel E, Krishnamurthy P, Miyasaka T, Liu L, Herman M, Kumar A, Bretteville A, Figueroa HY, Yu WH, Whittington RA, Davies P, Takashima A, Nixon RA, Duff KE. Anesthesia-induced hyperphosphorylation detaches 3-repeat tau from microtubules without affecting their stability in vivo. J Neurosci 2008; 28:12798-807. PMCID: PMC2610528
Yuan A, Sasaki T, Rao MV, Kumar A, Kanumuri V, Dunlop DS, Liem RK, Nixon RA. Neurofilaments form a highly stable stationary cytoskeleton after reaching a critical level in axons. J Neurosci 2009; 29:11316-29. PMCID: PMC Journal – In Process.
Okada H, Zhang W, Peterhoff C, Hwang J, Nixon R, Ryu SH, Kim T-W. Modulation of the beta-site APP cleaving enzyme-1 (BACE1) by Sorting Nexin 6. J Neurosci 2009 (in press).
Mi W, Jung SS, Yu WH, Schmidt SD, Nixon RA, Mathews PM, Tagliavini F, Levy E. Complexes of amyloid beta and cystatin C in human central nervous system. J Alzheimers Dis 2009 (in press) [Epub ahead of print].
Choi J, Berger JD, Mazzella MJ, Morales-Corraliza J, Cataldo AM, Nixon RA, Ginsberg SD, Levy E, Mathews PM. Age-dependent dysregulation of brain APP in the Ts65Dn Down syndrome mouse model. J Neurochem 2009 (in press) [Epub ahead of print].
Rao MV, Mohan P, Kumar A, Montagna L, Campbell J, Yuan D, Espreafico EM, Julien JP, Nixon RA. The Myosin Va head domain binds to the neurofilament-L rob and modulates local organelle content and distribution within axons. FASEB J (in press)
Invited Reviews and Chapters
Nixon RA. Neural circuitry and signaling in dementia and Alzheimer’s disease. In: Brain Circuitry and Signaling in Psychiatry: Basic Science and Clinical Implications. Kaplan GB and Hammer RP, Jr. (eds.) American Psychiatric Publishing, Inc., WDC, 2002; 201-226.
Nixon RA. Cell and molecular neuropathology of Alzheimer’s disease. In: Neuropsycho- pharmacology: The Fifth Generation of Progress; Davis KL, Charney D, Coyle JT, and Nemeroff C (eds.) American College of Neuropsychopharmacology 2002; Lippincott Williams & Wilkins, Philadelphia, PA.
Tatton W, Chen D, Chalmers-Redman R, Wheeler L, Nixon R, Tatton N. Nixon RA. Hypothesis for a common basis for neuroprotection in glaucoma and Alzheimer’s disease: anti-apoptosis by alpha-2-adrenergic receptor activation. Survey of Ophthalmology 2003; 48: Supplement 1 p:S25-S37.
Rao MV and Nixon RA. Defective neurofilament transport in mouse models of amyotrophic lateral sclerosis: A review. Neurochem Res 2003; 28:1041-1047.
Matthews PM, Nixon RA. Setback for an Alzheimer’s disease vaccine: Lessons learned. Neurology 2003; 61(1):7/8.
Nixon RA. The calpains in aging and aging-related diseases. Ageing Research Reviews 2003; 2:407-418.
Nixon RA. Niemann-Pick Type C disease and Alzheimer’s disease: The APP-endosome connection fattens up. American Journal of Pathology 2004; 164(3): 757-61.
Nixon RA. Endosome function and dysfunction in Alzheimer’s disease and other neurodegenerative diseases. Neurobiology of Aging 2005; 26:373-382.
Nixon RA and Cataldo AM. Lysosomal system pathways: Genes to neurodegeneration in Alzheimer’s disease. J Alzheimer’s Dis 2006; 7:1-13.
Nixon RA. Autophagy in Neurodegenerative Disease: Friend, Foe, or Turncoat? Trends in Neurosci 2006; 29:528-535.
Cataldo AM and Nixon RA. Neuronal trafficking in Alzheimer disease Niemann- Pick Type C disease.IN: Protein Trafficking in Neurons. Bean A (ed). Elsevier Neurosci, Elsevier Publications, Amsterdam, Netherlands, 2006; pp 391-411.
Nixon RA. Autophagy, amyloidogenesis and Alzheimer’s disease. J Cell Sci. 2007; 120:4081-4091 PMID: 18032783.
Nixon RA, Yang DS, Lee J-H. Neurodegenerative lysosomal disorders: A continuum from development to late age. Autophagy 2008; 4:590-599.
Yang DS, Lee J-H, Nixon RA. Monitoring autophagy in Alzheimer’s disease and related neurodegenerative diseases. Methods Enzymol 2009; 453:111-44.
Wilson DA, Nixon RA. Sniffing out a function for prion proteins. Nat Neurosci 2009; 12:7-8.