Panaiyur Mohan, Ph.D.

Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer
Maxwell, Christopher A; Benitez, Javier; Gomez-Baldo, Laia; Osorio, Ana; Bonifaci, Nuria; Fernandez-Ramires, Ricardo; Costes, Sylvain V; Guino, Elisabet; Chen, Helen; Evans, Gareth J R; Mohan, Pooja; Catala, Isabel; Petit, Anna; Aguilar, Helena; Villanueva, Alberto; Aytes, Alvaro; Serra-Musach, Jordi; Rennert, Gad; Lejbkowicz, Flavio; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Ripamonti, Carla B; Bonanni, Bernardo; Viel, Alessandra; Allavena, Anna; Bernard, Loris; Radice, Paolo; Friedman, Eitan; Kaufman, Bella; Laitman, Yael; Dubrovsky, Maya; Milgrom, Roni; Jakubowska, Anna; Cybulski, Cezary; Gorski, Bohdan; Jaworska, Katarzyna; Durda, Katarzyna; Sukiennicki, Grzegorz; Lubinski, Jan; Shugart, Yin Yao; Domchek, Susan M; Letrero, Richard; Weber, Barbara L; Hogervorst, Frans B L; Rookus, Matti A; Collee, J Margriet; Devilee, Peter; Ligtenberg, Marjolijn J; Luijt, Rob B van der; Aalfs, Cora M; Waisfisz, Quinten; Wijnen, Juul; Roozendaal, Cornelis E P van; Easton, Douglas F; Peock, Susan; Cook, Margaret; Oliver, Clare; Frost, Debra; Harrington, Patricia; Evans, D Gareth; Lalloo, Fiona; Eeles, Rosalind; Izatt, Louise; Chu, Carol; Eccles, Diana; Douglas, Fiona; Brewer, Carole; Nevanlinna, Heli; Heikkinen, Tuomas; Couch, Fergus J; Lindor, Noralane M; Wang, Xianshu; Godwin, Andrew K; Caligo, Maria A; Lombardi, Grazia; Loman, Niklas; Karlsson, Per; Ehrencrona, Hans; Wachenfeldt, Anna von; Barkardottir, Rosa Bjork; Hamann, Ute; Rashid, Muhammad U; Lasa, Adriana; Caldes, Trinidad; Andres, Raquel; Schmitt, Michael; Assmann, Volker; Stevens, Kristen; Offit, Kenneth; Curado, Joao; Tilgner, Hagen; Guigo, Roderic; Aiza, Gemma; Brunet, Joan; Castellsague, Joan; Martrat, Griselda; Urruticoechea, Ander; Blanco, Ignacio; Tihomirova, Laima; Goldgar, David E; Buys, Saundra; John, Esther M; Miron, Alexander; Southey, Melissa; Daly, Mary B; Schmutzler, Rita K; Wappenschmidt, Barbara; Meindl, Alfons; Arnold, Norbert; Deissler, Helmut; Varon-Mateeva, Raymonda; Sutter, Christian; Niederacher, Dieter; Imyamitov, Evgeny; Sinilnikova, Olga M; Stoppa-Lyonne, Dominique; Mazoyer, Sylvie; Verny-Pierre, Carole; Castera, Laurent; de Pauw, Antoine; Bignon, Yves-Jean; Uhrhammer, Nancy; Peyrat, Jean-Philippe; Vennin, Philippe; Fert Ferrer, Sandra; Collonge-Rame, Marie-Agnes; Mortemousque, Isabelle; Spurdle, Amanda B; Beesley, Jonathan; Chen, Xiaoqing; Healey, Sue; Barcellos-Hoff, Mary Helen; Vidal, Marc; Gruber, Stephen B; Lazaro, Conxi; Capella, Gabriel; McGuffog, Lesley; Nathanson, Katherine L; Antoniou, Antonis C; Chenevix-Trench, Georgia; Fleisch, Markus C; Moreno, Victor; Pujana, Miguel Angel
2011 Nov;9(11):e1001199-e1001199, PLoS biology
Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM
— id: 150852, year: 2011, vol: 9, page: e1001199, stat: Journal Article,

The Myosin Va Head Domain Binds to the Neurofilament-L Rod and Modulates Endoplasmic Reticulum (ER) Content and Distribution within Axons
Rao, Mala V; Mohan, Panaiyur S; Kumar, Asok; Yuan, Aidong; Montagna, Lee; Campbell, Jabbar; Espreafico, Enilza M; Julien, Jean P; Nixon, Ralph A
2011 ;6(2):e17087-e17087, PLoS ONE
The neurofilament light subunit (NF-L) binds to myosin Va (Myo Va) in neurons but the sites of interaction and functional significance are not clear. We show by deletion analysis that motor domain of Myo Va binds to the NF-L rod domain that forms the NF backbone. Loss of NF-L and Myo Va binding from axons significantly reduces the axonal content of ER, and redistributes ER to the periphery of axon. Our data are consistent with a novel function for NFs as a scaffold in axons for maintaining the content and proper distribution of vesicular organelles, mediated in part by Myo Va. Based on observations that the Myo Va motor domain binds to intermediate filament (IF) proteins of several classes, Myo Va interactions with IFs may serve similar roles in organizing organelle topography in different cell types
— id: 126479, year: 2011, vol: 6, page: e17087, stat: Journal Article,

Therapeutic effects of remediating autophagy failure in a mouse model of Alzheimer disease by enhancing lysosomal proteolysis
Yang, Dun-Sheng; Stavrides, Philip; Mohan, Panaiyur S; Kaushik, Susmita; Kumar, Asok; Ohno, Masuo; Schmidt, Stephen D; Wesson, Daniel W; Bandyopadhyay, Urmi; Jiang, Ying; Pawlik, Monika; Peterhoff, Corrinne M; Yang, Austin J; Wilson, Donald A; St George-Hyslop, Peter; Westaway, David; Mathews, Paul M; Levy, Efrat; Cuervo, Ana M; Nixon, Ralph A
2011 Jul 1;7(7):788-789, Autophagy
The extensive autophagic-lysosomal pathology in Alzheimer disease (AD) brain has revealed a major defect: in the proteolytic clearance of autophagy substrates. Autophagy failure contributes on several levels to AD pathogenesis and has become an important therapeutic target for AD and other neurodegenerative diseases. We recently observed broad therapeutic effects of stimulating autophagic-lysosomal proteolysis in the TgCRND8 mouse model of AD that exhibits defective proteolytic clearance of autophagic substrates, robust intralysosomal amyloid-beta peptide (Abeta) accumulation, extracellular beta-amyloid deposition and cognitive deficits. By genetically deleting the lysosomal cysteine protease inhibitor, cystatin B (CstB), to selectively restore depressed cathepsin activities, we substantially cleared Abeta, ubiquitinated proteins and other autophagic substrates from autolysosomes/lysosomes and rescued autophagic-lysosomal pathology, as well as reduced total Abeta40/42 levels and extracellular amyloid deposition, highlighting the underappreciated importance of the lysosomal system for Abeta clearance. Most importantly, lysosomal remediation prevented the marked learning and memory deficits in TgCRND8 mice. Our findings underscore the pathogenic significance of autophagic-lysosomal dysfunction in AD and demonstrate the value of reversing this dysfunction as an innovative therapeautic strategy for AD
— id: 134440, year: 2011, vol: 7, page: 788, stat: Journal Article,

Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits
Yang, Dun-Sheng; Stavrides, Philip; Mohan, Panaiyur S; Kaushik, Susmita; Kumar, Asok; Ohno, Masuo; Schmidt, Stephen D; Wesson, Daniel; Bandyopadhyay, Urmi; Jiang, Ying; Pawlik, Monika; Peterhoff, Corrinne M; Yang, Austin J; Wilson, Donald A; St George-Hyslop, Peter; Westaway, David; Mathews, Paul M; Levy, Efrat; Cuervo, Ana M; Nixon, Ralph A
2011 Jan;134(Pt 1):258-277, Brain
Autophagy, a major degradative pathway for proteins and organelles, is essential for survival of mature neurons. Extensive autophagic-lysosomal pathology in Alzheimer's disease brain contributes to Alzheimer's disease pathogenesis, although the underlying mechanisms are not well understood. Here, we identified and characterized marked intraneuronal amyloid-beta peptide/amyloid and lysosomal system pathology in the Alzheimer's disease mouse model TgCRND8 similar to that previously described in Alzheimer's disease brains. We further establish that the basis for these pathologies involves defective proteolytic clearance of neuronal autophagic substrates including amyloid-beta peptide. To establish the pathogenic significance of these abnormalities, we enhanced lysosomal cathepsin activities and rates of autophagic protein turnover in TgCRND8 mice by genetically deleting cystatin B, an endogenous inhibitor of lysosomal cysteine proteases. Cystatin B deletion rescued autophagic-lysosomal pathology, reduced abnormal accumulations of amyloid-beta peptide, ubiquitinated proteins and other autophagic substrates within autolysosomes/lysosomes and reduced intraneuronal amyloid-beta peptide. The amelioration of lysosomal function in TgCRND8 markedly decreased extracellular amyloid deposition and total brain amyloid-beta peptide 40 and 42 levels, and prevented the development of deficits of learning and memory in fear conditioning and olfactory habituation tests. Our findings support the pathogenic significance of autophagic-lysosomal dysfunction in Alzheimer's disease and indicate the potential value of restoring normal autophagy as an innovative therapeutic strategy for Alzheimer's disease
— id: 126481, year: 2011, vol: 134, page: 258, stat: Journal Article,

Cystatin C rescues degenerating neurons in a cystatin B-knockout mouse model of progressive myoclonus epilepsy
Kaur, Gurjinder; Mohan, Panaiyur; Pawlik, Monika; DeRosa, Steven; Fajiculay, Jay; Che, Shaoli; Grubb, Anders; Ginsberg, Stephen D; Nixon, Ralph A; Levy, Efrat
2010 Nov;177(5):2256-2267, American journal of pathology
In vitro studies have shown that cystatin C (CysC) is neuroprotective. Here we demonstrate that CysC is neuroprotective in vivo, in a mouse model of the inherited neurodegenerative disorder, progressive myoclonic epilepsy type 1 (EPM1). Loss-of-function mutations in the cystatin B (CysB) gene, an intracellular cysteine protease inhibitor, lead to this human disease. A CysB-knockout (CysBKO) mouse model develops symptoms that mimic EPM1. CysB deficiency in these mice results in enhanced cathepsin B and D activities, indicating lysosomal dysfunction. We show that expression of CysC is enhanced in the brains of CysBKO mice. Crossbreeding of CysBKO mice with either CysC-overexpressing transgenic mice or CysC-knockout mice demonstrates that clinical symptoms and neuropathologies, including motor coordination disorder, cerebellar atrophy, neuronal loss in the cerebellum and cerebral cortex, and gliosis caused by CysB deficiency, are rescued by CysC overexpression and exacerbated by CysC deficiency. Thus, CysC effectively rescues the CysB loss-of-function mutations, facilitating the reversal of pathophysiological changes and suggesting a novel therapeutic intervention for patients with EPM1 and other neurodegenerative disorders
— id: 126484, year: 2010, vol: 177, page: 2256, stat: Journal Article,

Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations
Lee, Ju-Hyun; Yu, W Haung; Kumar, Asok; Lee, Sooyeon; Mohan, Panaiyur S; Peterhoff, Corrinne M; Wolfe, Devin M; Martinez-Vicente, Marta; Massey, Ashish C; Sovak, Guy; Uchiyama, Yasuo; Westaway, David; Cuervo, Ana Maria; Nixon, Ralph A
2010 Jun 25;141(7):1146-1158, Cell
Macroautophagy is a lysosomal degradative pathway essential for neuron survival. Here, we show that macroautophagy requires the Alzheimer's disease (AD)-related protein presenilin-1 (PS1). In PS1 null blastocysts, neurons from mice hypomorphic for PS1 or conditionally depleted of PS1, substrate proteolysis and autophagosome clearance during macroautophagy are prevented as a result of a selective impairment of autolysosome acidification and cathepsin activation. These deficits are caused by failed PS1-dependent targeting of the v-ATPase V0a1 subunit to lysosomes. N-glycosylation of the V0a1 subunit, essential for its efficient ER-to-lysosome delivery, requires the selective binding of PS1 holoprotein to the unglycosylated subunit and the Sec61alpha/oligosaccharyltransferase complex. PS1 mutations causing early-onset AD produce a similar lysosomal/autophagy phenotype in fibroblasts from AD patients. PS1 is therefore essential for v-ATPase targeting to lysosomes, lysosome acidification, and proteolysis during autophagy. Defective lysosomal proteolysis represents a basis for pathogenic protein accumulations and neuronal cell death in AD and suggests previously unidentified therapeutic targets
— id: 126485, year: 2010, vol: 141, page: 1146, stat: Journal Article,

Induction of autophagy by cystatin C: a mechanism that protects murine primary cortical neurons and neuronal cell lines
Tizon, Belen; Sahoo, Susmita; Yu, Haung; Gauthier, Sebastien; Kumar, Asok R; Mohan, Panaiyur; Figliola, Matthew; Pawlik, Monika; Grubb, Anders; Uchiyama, Yasuo; Bandyopadhyay, Urmi; Cuervo, Ana Maria; Nixon, Ralph A; Levy, Efrat
2010 ;5(3):e9819-e9819, PLoS ONE
Cystatin C (CysC) expression in the brain is elevated in human patients with epilepsy, in animal models of neurodegenerative conditions, and in response to injury, but whether up-regulated CysC expression is a manifestation of neurodegeneration or a cellular repair response is not understood. This study demonstrates that human CysC is neuroprotective in cultures exposed to cytotoxic challenges, including nutritional-deprivation, colchicine, staurosporine, and oxidative stress. While CysC is a cysteine protease inhibitor, cathepsin B inhibition was not required for the neuroprotective action of CysC. Cells responded to CysC by inducing fully functional autophagy via the mTOR pathway, leading to enhanced proteolytic clearance of autophagy substrates by lysosomes. Neuroprotective effects of CysC were prevented by inhibiting autophagy with beclin 1 siRNA or 3-methyladenine. Our findings show that CysC plays a protective role under conditions of neuronal challenge by inducing autophagy via mTOR inhibition and are consistent with CysC being neuroprotective in neurodegenerative diseases. Thus, modulation of CysC expression has therapeutic implications for stroke, Alzheimer's disease, and other neurodegenerative disorders
— id: 109506, year: 2010, vol: 5, page: e9819, stat: Journal Article,

Marked calpastatin (CAST) depletion in Alzheimer's disease accelerates cytoskeleton disruption and neurodegeneration: neuroprotection by CAST overexpression
Rao, Mala V; Mohan, Panaiyur S; Peterhoff, Corrinne M; Yang, Dun-Sheng; Schmidt, Stephen D; Stavrides, Philip H; Campbell, Jabbar; Chen, Yuanxin; Jiang, Ying; Paskevich, Peter A; Cataldo, Anne M; Haroutunian, Vahram; Nixon, Ralph A
2008 Nov 19;28(47):12241-12254, Journal of neuroscience
Increased activity of calpains is implicated in synaptic dysfunction and neurodegeneration in Alzheimer's disease (AD). The molecular mechanisms responsible for increased calpain activity in AD are not known. Here, we demonstrate that disease progression is propelled by a marked depletion of the endogenous calpain inhibitor, calpastatin (CAST), from AD neurons, which is mediated by caspase-1, caspase-3, and calpains. Initial CAST depletion focally along dendrites coincides topographically with calpain II and ERK 1/2 activation, tau cleavage by caspase-3, and tau and neurofilament hyperphosphorylation. These same changes, together with cytoskeletal proteolysis and neuronal cell death, accompany CAST depletion after intrahippocampal kainic acid administration to mice, and are substantially reduced in mice overexpressing human CAST. Moreover, CAST reduction by shRNA in neuronal cells causes calpain-mediated death at levels of calcium-induced injury that are sublethal to cells normally expressing CAST. Our results strongly support a novel hypothesis that CAST depletion by multiple abnormally activated proteases accelerates calpain dysregulation in AD leading to cytoskeleton disruption and neurodegeneration. CAST mimetics may, therefore, be neuroprotective in AD
— id: 94362, year: 2008, vol: 28, page: 12241, stat: Journal Article,

Mesencephalic dopamine neuron number and tyrosine hydroxylase content: Genetic control and candidate genes
Vadasz, C; Smiley, J F; Figarsky, K; Saito, M; Toth, R; Gyetvai, B M; Oros, M; Kovacs, K K; Mohan, P; Wang, R
2007 Nov 9;149(3):561-572, Neuroscience
The mesotelencephalic dopamine system shows substantial genetic variation which fundamentally affects normal and pathological behaviors related to motor function, motivation, and learning. Our earlier radioenzyme assay studies demonstrated significantly higher activity of tyrosine hydroxylase (TH), the first and rate limiting enzyme in the biosynthesis of catecholamine neurotransmitters, in the substantia nigra-ventral tegmental area of BALB/cJ mice in comparison with that of C57BL/6ByJ mice. Here, using quantitative immunoblotting and immunocytochemistry, we tested the hypothesis that mesencephalic TH protein content and number of nigral TH-positive neurons show strain-dependent differences in C57BL/6ByJ and BALB/cJ parallel to those observed in the TH activity studies. Immunoblotting experiments detected significantly higher mesencephalic TH protein content in BALB/cJ in comparison to C57BL/6ByJ (P<0.05). Immunocytochemical studies demonstrated that the number of TH-positive cells in substantia nigra was 31.3% higher in BALB/cJ than that in C57BL/6ByJ (P<0.01), while the average dopamine neuron volume was not significantly different. In a search for candidate genes that modulate TH content and the size of mesencephalic dopamine neuron populations we also studied near-isogenic mouse sublines derived from the C57BL/6ByJ and BALB/cJ progenitor strains. A whole-genome scan with 768 single nucleotide polymorphism markers indicated that two sublines, C4A6/N and C4A6/B, were genetically very similar (98.3%). We found significantly higher mesencephalic TH protein content in C4A6/B in comparison to C4A6/N (P=0.01), and a tendency for higher number of dopamine neurons in the substantia nigra in C4A6/B in comparison to C4A6/N, which, however, did not reach statistical significance. To identify the genetic source of the TH content difference we analyzed the single nucleotide polymorphism (SNP) genotype data of the whole-genome scan, and detected two small differential chromosome segments on chr. 13 and chr. 14. Microarray gene expression studies and bioinformatic analysis of the two differential regions implicated two cis-regulated genes (Spock1 and Cxcl14, chr. 13), and two growth factor genes [bone morphogenetic protein 6 (Bmp6) (chr. 13), and fibroblast growth factor 14 (Fgf14) (chr. 14)]. Taken together, the results suggest that (1) nigral dopamine neuron number and TH protein content may be genetically associated but further studies are needed to establish unequivocally this linkage, and (2) Spock1, Cxcl14, Bmp6, and Fgf14 are novel candidates for modulating the expression and maintenance of TH content in mesencephalic dopamine neurons in vivo
— id: 75475, year: 2007, vol: 149, page: 561, stat: Journal Article,

Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease
Yu, W Haung; Cuervo, Ana Maria; Kumar, Asok; Peterhoff, Corrinne M; Schmidt, Stephen D; Lee, Ju-Hyun; Mohan, Panaiyur S; Mercken, Marc; Farmery, Mark R; Tjernberg, Lars O; Jiang, Ying; Duff, Karen; Uchiyama, Yasuo; Naslund, Jan; Mathews, Paul M; Cataldo, Anne M; Nixon, Ralph A
2005 Oct 10;171(1):87-98, Journal of cell biology
Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before beta-amyloid (Abeta) deposits extracellularly in the presenilin (PS) 1/Abeta precursor protein (APP) mouse model of beta-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Abeta. Purified AVs contain APP and beta-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent gamma-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Abeta production. Our results, therefore, link beta-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD
— id: 60255, year: 2005, vol: 171, page: 87, stat: Journal Article,

Autophagy in Alzheimer's disease pathogenesis
Nixon, RA; Yu, WH; Cuervo, AM; Cataldo, AM; Mathews, PM; Yang, DS; Zheng, P; Peterhoff, CM; Kumar, A; Jiang, Y; Peterson, J; Schmidt, SD; Mohan, P; Duff, K; Hassinger, L; Wegiel, J; Lamb, B
2004 JUL ;25(10):S70-S71, Neurobiology of aging
— id: 47716, year: 2004, vol: 25, page: S70, stat: Journal Article,

AD-related cathepsin D overexpression promotes mitochondrial-dependent apoptosis
Ping, Z; Jiang, Y; Mohan, PS; Mathews, PM; Nixon, RA
2004 JUL ;25(10):S438-S438, Neurobiology of aging
— id: 47739, year: 2004, vol: 25, page: S438, stat: Journal Article,

Calpain mediates calcium-induced activation of the erk1,2 MAPK pathway and cytoskeletal phosphorylation in neurons: relevance to Alzheimer's disease
Veeranna; Kaji T; Boland B; Odrljin T; Mohan P; Basavarajappa BS; Peterhoff C; Cataldo A; Rudnicki A; Amin N; Li BS; Pant HC; Hungund BL; Arancio O; Nixon RA
2004 Oct;165(3):795-805, American journal of pathology
Aberrant phosphorylation of the neuronal cytoskeleton is an early pathological event in Alzheimer's disease (AD), but the underlying mechanisms are unclear. Here, we demonstrate in the brains of AD patients that neurofilament hyperphosphorylation in neocortical pyramidal neurons is accompanied by activation of both Erk1,2 and calpain. Using immunochemistry, Western blot analysis, and kinase activity measurements, we show in primary hippocampal and cerebellar granule (CG) neurons that calcium influx activates calpain and Erk1,2 and increases neurofilament phosphorylation on carboxy terminal polypeptide sites known to be modulated by Erk1,2 and to be altered in AD. Blocking Erk1,2 activity either with antisense oligonucleotides to Erk1,2 mRNA sequences or by specifically inhibiting its upstream activating kinase MEK1,2 markedly reduced neurofilament phosphorylation. Calpeptin, a cell-permeable calpain inhibitor, blocked both Erk1,2 activation and neurofilament hyperphosphorylation at concentrations that inhibit calpain-mediated cleavage of brain spectrin. By contrast, inhibiting Erk1,2 with U-0126, a specific inhibitor of Mek1,2, had no appreciable effect on ionomycin-induced calpain activation. These findings demonstrate that, under conditions of calcium injury in neurons, calpains are upstream activators of Erk1,2 signaling and are likely to mediate in part the hyperphosphorylation of neurofilaments and tau seen at early stages of AD as well as the neuron survival-related functions of the MAP kinase pathway
— id: 46128, year: 2004, vol: 165, page: 795, stat: Journal Article,

Calpain mediates calcium-induced activation of the ERK 1,2 MAPK pathway and cytoskeletal phosphorylation in neurons: Relevance to Alzheimer's disease
Veeranna; Kaji, T; Boland, B; Odrljin, T; Mohan, P; Basavarajappa, BS; Peterhoff, C; Cataldo, AM; Rudnicki, A; Li, BS; Pant, HC; Hungund, BL; Arancio, O; Nixon, RA
2004 JUL ;25(10):S173-S173, Neurobiology of aging
— id: 47723, year: 2004, vol: 25, page: S173, stat: Journal Article,

Calpain activation in neurodegenerative diseases
Adamec, E; Mohan, P; Nixon, RA; Vonsattel, JP
2002 Jul-Aug;23(1S):S245- Abstract #918, Neurobiology of aging
— id: 32421, year: 2002, vol: 23, page: S245, stat: Journal Article,

Calpain activation in neurodegenerative diseases: confocal immunofluorescence study with antibodies specifically recognizing the active form of calpain 2
Adamec, Emil; Mohan, Panaiyur; Vonsattel, Jean P; Nixon, Ralph A
2002 Jul;104(1):92-104, Acta neuropathologica
The calcium-activated protease calpain cleaves a variety of biologically important proteins and serves, therefore, as a key regulator of many cellular functions. Activation of both main isoforms, calpain 1 and calpain 2, was demonstrated previously in Alzheimer's disease. In this report, antibodies specifically recognizing the active form of calpain 2 were used to investigate calpain 2 activation in a broad range of neurodegenerative diseases, utilizing multiple-label confocal immunofluorescence imaging. With rare exceptions, the active form of calpain 2 was found in colocalization with hyperphosphorylated tau protein. Aggregates of mutated huntingtin, alpha-synuclein, or unidentified protein in motor neuron disease type of frontotemporal dementia were always negative. These findings indicate that calpain 2 activation is not a general response to protein aggregation. In tauopathies, more pathological inclusions were labeled for hyperphosphorylated tau than for activated calpain 2. The extent of colocalization varied in both a disease-specific and cell-type specific manner. The active form of calpain 2 was detected in 50-75% of tau neurofibrillary pathology in Alzheimer's disease, Alzheimer neurofibrillary changes and Down's syndrome, as well as in the accompanying Alzheimer-type tau pathology in diffuse Lewy bodies disease, progressive supranuclear palsy, and corticobasal degeneration. For glial cells, only 10-25% of tuft-shaped astrocytes, glial plaques, or coiled bodies contained activated calpain 2. The majority of Pick bodies were negative. The association of calpain 2 activation with hyperphosphorylated tau might be the result of an attempt by the calpain proteolytic system to degrade the tau protein aggregates. Alternatively, calpain 2 could be directly involved in tau hyperphosphorylation by modulating protein kinase activities. Overall, these results provide evidence of the important role of the calpain proteolytic system in the pathogenesis of neurodegenerative diseases with tau neurofibrillary pathology
— id: 32532, year: 2002, vol: 104, page: 92, stat: Journal Article,

Autophagic cell death: Relevance to Alzheimer disease neurodegeneration
Nixon, RA; Mathews, PM; Ginsberg, SD; Duff, K; Mohan, P; Cataldo, AM; Wegiel, J; Yu, WH; Schmidt, SD; Jacobsen, SP; Peterhoff, CM; Terio, N; Keller, JN; Hassinger, L
2002 Jul-Aug;23(1):1527-, Neurobiology of aging
— id: 32429, year: 2002, vol: 23, page: 1527, stat: Journal Article,

Myosin Va binding to neurofilaments is essential for correct myosin Va distribution and transport and neurofilament density
Rao, Mala V; Engle, Linda J; Mohan, Panaiyur S; Yuan, Aidong; Qiu, Dike; Cataldo, Anne; Hassinger, Linda; Jacobsen, Stephen; Lee, Virginia M-Y; Andreadis, Athena; Julien, Jean-Pierre; Bridgman, Paul C; Nixon, Ralph A
2002 Oct 28;159(2):279-290, Journal of cell biology
The identification of molecular motors that modulate the neuronal cytoskeleton has been elusive. Here, we show that a molecular motor protein, myosin Va, is present in high proportions in the cytoskeleton of mouse CNS and peripheral nerves. Immunoelectron microscopy, coimmunoprecipitation, and blot overlay analyses demonstrate that myosin Va in axons associates with neurofilaments, and that the NF-L subunit is its major ligand. A physiological association is indicated by observations that the level of myosin Va is reduced in axons of NF-L-null mice lacking neurofilaments and increased in mice overexpressing NF-L, but unchanged in NF-H-null mice. In vivo pulse-labeled myosin Va advances along axons at slow transport rates overlapping with those of neurofilament proteins and actin, both of which coimmunoprecipitate with myosin Va. Eliminating neurofilaments from mice selectively accelerates myosin Va translocation and redistributes myosin Va to the actin-rich subaxolemma and membranous organelles. Finally, peripheral axons of dilute-lethal mice, lacking functional myosin Va, display selectively increased neurofilament number and levels of neurofilament proteins without altering axon caliber. These results identify myosin Va as a neurofilament-associated protein, and show that this association is essential to establish the normal distribution, axonal transport, and content of myosin Va, and the proper numbers of neurofilaments in axons
— id: 32536, year: 2002, vol: 159, page: 279, stat: Journal Article,

In vivo perturbation of lysosomal function promotes neurodegeneration in the PS1m146V/APPPK67ON,M671L mouse model of Alzheimer's disease pathology
Nixon RA; Mathews PM; Cataldo AM; Mohan PS; Schmidt SD; Duff K; Berg M; Marks N; Peterhoff C; Sershen H
Alzheimer's disease: advances in etiology, pathogenesis and therapeutics Chichester: Wiley, 2001,
— id: 2654, year: 2001, vol: , page: , stat: Chapter,

Experimental aging of the lysosomal system promotes neurodegeneration in the PS/APP mouse model of Alzheimer's disease pathology
Nixon, R. A.; Mathews, P. M.; Cataldo, A. M.; Mohan, P. S.; Marks, N.; Duff, K.; Berg, M.; Schmidt, S. D.; Jacobsen, S. P.; Jiang, Y.; Sershen, H.
2001 ;27(1):925-925, Abstracts (Society for Neuroscience)
The lysosomal system (LS) is markedly activated in vulnerable neuronal populations early in Alzheimer's disease, although lysosomes become less efficient degradative compartments as neurons become more compromised. LS dysfunction, especially altered activity of the lysosomal protease cathepsin D, has been implicated in cell death initiation under various apoptotic conditions in vivo and in vitro. In this study, we observed that cathepsin D content increases nearly 3-fold in the human neocortex during normal aging while lysosomal cysteine protease activities decrease. By contrast, during aging in the mouse, this protease imbalance and other aging-related changes of the LS, such as lipofuscin accumulation, are minimal in these cortical areas. However, when leupeptin (a cysteine protease inhibitor) was infused intraventricularly, an imbalance of cathepsins similar to that in the aging human brain was induced. This was accompanied by changes associated with cell senescence, including ceroid-lipofuscin accumulation and alterations of tau proteolysis. In PSM146L/APPSWE transgenic mice, super-imposition of this aging-related cathepsin imbalance accentuated preexisting LS abnormalities to the level seen in AD brain and also induced neuronal atrophy and neurodegeneration. The minimal degree of 'lysosomal aging' seen in old mice, compared to that in humans, may partly explain the mild neurodegenerative phenotypes in transgenic models of AD pathology. In addition, these studies provide in vivo evidence relating altered lysosomal function to neurodegeneration
— id: 115690, year: 2001, vol: 27, page: 925, stat: Journal Article,

Up-regulation of the lysosomal system in experimental models of neuronal injury: implications for Alzheimer's disease
Adamec E; Mohan PS; Cataldo AM; Vonsattel JP; Nixon RA
2000 ;100(3):663-675, Neuroscience
Previous studies established that the populations of neurons that frequently degenerate in Alzheimer's disease exhibit robust up-regulation of the lysosomal system. In this study, we investigated alterations of the lysosomal system during different forms of experimental injury in rat hippocampal neurons in culture, utilizing a combination of immunocytochemical and biochemical methods. Using triple-label immnocytochemistry for activated caspase-3, fragmentation of DNA and the microtubule-associated protein-2, we characterized treatment paradigms as models of the apoptotic (staurosporine, camptothecin), the oncotic (high-dose menadione, glutamate), and the mixed apoptotic and oncotic (low-dose menadione) pathways of neuronal death. Slowly developing apoptotic or slowly developing mixed apoptotic and oncotic forms of neuronal injury were associated with substantial increases in the number and size of cathepsin D-positive vesicles (late endosomes and mature lysosomes) as determined by immunocytochemistry, and elevated levels of cathepsin D by western blotting. In agreement with our previous findings in Alzheimer's disease, where lysosomal system activation was not restricted to overtly degenerating neurons, up-regulation of this system was also detected quite early during the course of experimental neuronal injury, preceding the development of dystrophic neurites, nuclear segmentation or fragmentation of DNA. These findings implicate lysosomal system activation, both in Alzheimer's disease and in experimental models of neuronal injury, as an important event associated with early stages of neurodegeneration
— id: 24717, year: 2000, vol: 100, page: 663, stat: Journal Article,

The lysosomal system and neurodegeneration in Alzheimer disease and related disorders
Nixon, R; Mathews, P; Cataldo, A; Mohan, P; Yang, A; Adamec, E; Duff, K
2000 FEB ;74(2):S42-S42, Journal of neurochemistry
— id: 54744, year: 2000, vol: 74, page: S42, stat: Journal Article,

Local control of neurofilament accumulation during radial growth of myelinating axons in vivo. Selective role of site-specific phosphorylation
Sanchez I; Hassinger L; Sihag RK; Cleveland DW; Mohan P; Nixon RA
2000 Nov 27;151(5):1013-1024, Journal of cell biology
The accumulation of neurofilaments required for postnatal radial growth of myelinated axons is controlled regionally along axons by oligodendroglia. Developmentally regulated processes previously suspected of modulating neurofilament number, including heavy neurofilament subunit (NFH) expression, attainment of mature neurofilament subunit stoichiometry, and expansion of interneurofilament spacing cannot be primary determinants of regional accumulation as we show each of these factors precede accumulation by days or weeks. Rather, we find that regional neurofilament accumulation is selectively associated with phosphorylation of a subset of Lys-Ser-Pro (KSP) motifs on heavy neurofilament subunits and medium-size neurofilament subunits (NFMs), rising >50-fold selectively in the expanding portions of optic axons. In mice deleted in NFH, substantial preservation of regional neurofilament accumulation was accompanied by increased levels of the same phosphorylated KSP epitope on NFM. Interruption of oligodendroglial signaling to axons in Shiverer mutant mice, which selectively inhibited this site-specific phosphorylation, reduced regional neurofilament accumulation without affecting other neurofilament properties or aspects of NFH phosphorylation. We conclude that phosphorylation of a specific KSP motif triggered by glia is a key aspect of the regulation of neurofilament number in axons during axonal radial growth
— id: 24723, year: 2000, vol: 151, page: 1013, stat: Journal Article,

Calpain modulates secretion of soluble APP in human retinoblastoma (Y-79) cells
Mohan, P S; Terio, N; Achilleos, M; Nixon, R A
1999 Oct 23-28;25(1-2):1105-1105, Abstracts (Society for Neuroscience)
— id: 15847, year: 1999, vol: 25, page: 1105, stat: Journal Article,

Calpains in the pathogenesis of Alzheimer's disease
Nixon RA; Mohan PS
Calpain: pharmacology and toxicology of calcium-dependent protease Philadelphia : Taylor & Francis, 1999,
— id: 2660, year: 1999, vol: , page: 267, stat: Chapter,

Caspase-mediated fragmentation of calpain inhibitor protein calpastatin during apoptosis
Wang KK; Posmantur R; Nadimpalli R; Nath R; Mohan P; Nixon RA; Talanian RV; Keegan M; Herzog L; Allen H
1998 Aug 15;356(2):187-196, Archives of biochemistry & biophysics. ABB
Two cysteine protease families (caspase and calpain) participate in apoptosis. Here we report that the endogenous calpain inhibitor calpastatin is fragmented by caspase(s) to various extents during early apoptosis in two cell types. In anti-fas or staurosporine-treated Jurkat T-cells, the high-molecular-weight form (HMW) of calpastatin (apparent Mr 110 K) was extensively degraded to immunoreactive fragments of Mr 75 K and 30 K In apoptotic SH-SY5Y human neuroblastoma cells, HMW calpastatin was degraded to a major immunoreactive fragment of 75 K. In both cell types, fragmentation of HMW calpastatin was blocked by a caspase-specific inhibitor carbobenzoxy-Asp-CH2OC(O)-2,6-dichlorobenzene. In vitro translated HMW calpastatin was sensitive to proteolysis by recombinant caspase-1, -3, and -7. By contrast, in vitro translated LMW calpastatin (which lacks domains L and I) was cleaved into multiple fragments only by caspase-1 and was relatively resistant to caspase-3, -7, and other caspases tested. Consistently with that, purified erythroid LMW calpastatin was also highly susceptible to caspase-1 digestion. Recombinant human calpastatin spanning domain I through III (CAST(DI-III)) was found cleaved by caspase-1 at at least three sites, located in either the A or the C helix of domains I and III (ALDD137*L, LSSD203*F and ALAD404*S), while only a single site (ALDD137*L) was cleaved by caspase-3. These findings suggest that both HMW and LMW calpastatins are more vulnerable to caspase-1 than to caspase-3. Surprisingly, both erythroid LMW calpastatin and recombinant CAST(DI-III) fragmented by caspase-1 suffered only a less than twofold reduction of inhibitory activity toward calpain. We propose that the proteolysis of calpastatin in early apoptosis might have yet unidentified effects on the cross-talk between the two protease systems.
— id: 7948, year: 1998, vol: 356, page: 187, stat: Journal Article,

Calpains and calpastatin in SH-SY5Y neuroblastoma cells during retinoic acid-induced differentiation and neurite outgrowth: comparison with the human brain calpain system
Grynspan F; Griffin WB; Mohan PS; Shea TB; Nixon RA
1997 May 1;48(3):181-191, Journal of neuroscience research
Calpains have importance in human neurodegenerative disease pathogenesis, but these mechanisms are difficult to study in postmortem tissues. To establish a cellular model of the human calpain and calpastatin system, we characterized calpain I, calpain II, and calpastatin in SH-SY5Y human neuroblastoma cells in relation to their counterparts in human brain and investigated their expression and activity after inducing cellular differentiation with retinoic acid (RA), a physiological effector of normal brain development. Calpain I in both SH-SY5Y cells and human brain existed in the cytosolic and particulate fractions as three isoforms (80, 78, and 76 kDa) and exhibited atypical isoelectric focusing behavior. Calpain II in SH-SY5Y cells, as in human brain, migrated as a single predominantly cytosolic 76-kDa protein with an isoelectric point ranging from 5.9 to 6.3. Calpastatin from both sources was also 90% cytosolic. In the cells it was composed of four discrete bands, ranging in molecular weight from 110 to 127 kDa. Levels of activated (76 and 78 kDa) and precursor (80 kDa) calpain I isoforms rose 54% (P < 0.0001) in the particulate fraction and 26% (P < 0.0001) in the soluble fraction after 3 days of RA exposure. Because levels and activity of calpastatin remain unchanged during the first 7 days of RA exposure, the increased abundance of calpain I implies a net activation of the calpain system during differentiation. Calpain I activation may contribute to the remodeling of cell shape and neurite extension/retraction associated with neuronal differentiation
— id: 24718, year: 1997, vol: 48, page: 181, stat: Journal Article,

Limited proteolytic processing of the mature form of cathepsin D in human and mouse brain: postmortem stability of enzyme structure and activity
Compaine A; Schein JD; Tabb JS; Mohan PS; Nixon RA
1995 Oct-Nov;27(4-5):385-396, Neurochemistry international
The mature form of cathepsin D (Cat D), purified to homogeneity from postmortem human brain or mouse brain, behaved as a 42-kDa protein in its native state but revealed additional proteolytic processing under denaturing conditions. Human brain Cat D was composed of a 30-32 kDa heavy chain and a protein doublet consisting of 14 and 15 kDa light chains. Mouse Cat D, which closely resembled the human enzyme in amino acid composition, existed mainly as the uncleaved 42-kDa protein, but up to 40% existed as a complex of 30-32 kDa and 12-14 kDa chains. The 3:1 ratio of light to heavy (30-32 kDa) chains suggested processing of some 30-kDa chains. Cleavage of the 42-kDa chain could not be induced autolytically. Human brain Cat D had a 2-3-fold higher specific activity than the mouse enzyme but shared other properties, including similar biphasic pH optima (peaks at pH 3.30 and 4.2), Km values for methemoglobin and inhibitor profiles. Human Cat D displayed the same polypeptide chain composition when purified from brains differing in postmortem interval (3-28 h). Fresh SH-SY5Y human neuroblastoma cells analyzed on Western blots with anti-Cat D antibodies also displayed only cleaved forms of mature Cat D. Furthermore, brain Cat D isolated from mice stored after death for 5, 15 or 30 h at 25 degrees C contained the same molar ratios of cleaved and uncleaved enzyme found in fresh mouse brain . Cat D activity was stable in human brains with postmortem intervals up to 27 h and stored frozen for up to 3 years. Similarly, total Cat D activity was essentially unchanged in brains of mice subjected to stimulated postmortem conditions for 0.5-4.2 h, although 20% of the total soluble brain protein became insoluble during this postmortem interval. These results demonstrate a remarkable postmortem stability of Cat D and strongly suggest that limited proteolytic cleavage of mature brain Cat D is an in vivo event, the extent of which varies markedly in different species
— id: 24719, year: 1995, vol: 27, page: 385, stat: Journal Article,

Proteolysis of protein kinase C: mM and microM calcium-requiring calpains have different abilities to generate, and degrade the free catalytic subunit, protein kinase M
Cressman CM; Mohan PS; Nixon RA; Shea TB
1995 Jul 3;367(3):223-227, FEBS letters
Limited proteolysis of protein kinase C (PKC) by calpain under cell free conditions cleaves the regulatory and catalytic PKC subunits, generating a free, co-factor independent catalytic subunit, termed PKM. In the present study, we demonstrate distinct differences in the rate, nature, and lipid-sensitivity of PKC and PKM proteolysis by microM and mM calcium-requiring calpain isozymes (mu calpain or m calpain, respectively). PKC is a preferred substrate for m calpain; not even a 100-fold increase in mu calpain was capable of degrading PKC as fast as in calpain. PKM was generated by both m and mu calpains, but was itself rapidly degraded by m calpain and therefore was only transiently detectable. By contrast, PKM was formed but not degraded by mu calpain, and persisted in the presence of mu calpain long after all PKC had been degraded. Phosphatidyl serine (PS) inhibited PKC hydrolysis by m calpain yet enhanced PKC hydrolysis by mu calpain. The ability of either calpain isoenzyme to degrade [14C]azocasein was unaffected by PS, suggesting that the influence of PS was on PKC conformation. These findings point towards distinct roles for mu and m calpain in PKC regulation
— id: 24720, year: 1995, vol: 367, page: 223, stat: Journal Article,

Purification and properties of high molecular weight calpastatin from bovine brain
Mohan PS; Nixon RA
1995 Feb;64(2):859-866, Journal of neurochemistry
Calcium-activated neutral proteases (calpains) are regulated by specific endogenous protein inhibitors, the calpastatins, which are widely distributed in mammalian tissues. Calpastatins from different species or in various tissues from the same species exhibit considerable size heterogeneity on sodium dodecyl sulfate (SDS) gels, reflecting both transcriptional and posttranslational regulation. This heterogeneity has complicated previous biochemical characterizations. In this study, we purified bovine brain calpastatin to homogeneity. The inhibitor was purified 2,463-fold from a cytosolic fraction of fresh bovine cerebral cortex by chromatographies on diethylaminoethyl cellulose, Ultrogel AcA44, phenyl-Sepharose, concanavalin A-Sepharose, and Q-Sepharose. The major calpastatin displayed a native molecular mass of 250-300 kDa by gel filtration and was composed of 125-kDa polypeptide chains by SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Small amounts of a 68-kDa calpastatin fragment were detected particularly in molecules exhibiting smaller native molecular mass (250 kDa). When electroeluted from SDS gels, the 125- and 68-kDa polypeptides each inhibited calpain. The purified protein was strongly immunoreactive toward antibodies raised against a synthetic peptide, CEKLGEKEETIPPDYR, shown to be a conserved repetitive motif in the calpastatin gene or a recombinant polypeptide corresponding to domains L and 1 of human calpastatin. Calpastatins purified from bovine and human erythrocytes exhibited molecular masses of 78 and 68 kDa, respectively, by SDS-PAGE. Both erythrocyte calpastatins reacted strongly with antibodies against the conserved sequence but not with antibodies raised against domains L and 1 of human calpastatin, indicating that the erythrocyte inhibitors lack these two domains.(ABSTRACT TRUNCATED AT 250 WORDS)
— id: 24721, year: 1995, vol: 64, page: 859, stat: Journal Article,

Elevated levels of the endosomal-lysosomal proteinase cathepsin D in cerebrospinal fluid in Alzheimer disease
Schwagerl AL; Mohan PS; Cataldo AM; Vonsattel JP; Kowall NW; Nixon RA
1995 Jan;64(1):443-446, Journal of neurochemistry
Lysosomal hydrolases are normally intracellular enzymes but are abundant extracellularly within senile plaques in Alzheimer disease and in other conditions where beta-amyloid accumulates. To examine whether acid hydrolases released from abnormal hydrolase-laden neurons are detectable in CSF, we measured levels of the major aspartic proteinase of lysosomes, cathepsin D (Cat D), in ventricular CSF collected after death from 30 patients with Alzheimer disease, 14 patients with Huntington disease, and seven patients with other neurodegenerative diseases. The levels of Cat D-immunoreactive protein, expressed as micrograms per milliliter of protein, determined by western blot immunoassay using a polyclonal antiserum against human brain Cat D, were more than fourfold higher in the Alzheimer patients than in the other patient groups (p < 0.0005). Cat D activity, assayed separately against [14C]methemoglobin at pH 3.2, was also significantly elevated but less than Cat D content. The lower specific activity of Cat D in Alzheimer CSF therefore indicated that the abnormally accumulated Cat D included a high proportion of inactive enzyme. These results indicate that abnormal Cat D release from affected neurons into the extracellular space is an active, ongoing process in Alzheimer brain. In addition, the levels of this enzyme and possibly other lysosomal hydrolases in CSF may prove to be useful biological markers of Alzheimer disease
— id: 24722, year: 1995, vol: 64, page: 443, stat: Journal Article,

Calcium-activated neutral proteinase (calpain) system in aging and Alzheimer's disease
Nixon RA; Saito KI; Grynspan F; Griffin WR; Katayama S; Honda T; Mohan PS; Shea TB; Beermann M
1994 Dec 15;747(3):77-91, Annals of the New York Academy of Sciences
Calpains (CANPs) are a family of calcium-dependent cysteine proteases under complex cellular regulation. By making selective limited proteolytic cleavages, they activate or alter the regulation of certain enzymes, including key protein kinases and phosphatases, and induce specific cytoskeletal rearrangements, accounting for their suspected involvement in intracellular signaling, vesicular trafficking, and structural stabilization. Calpain activity has been implicated in various aging phenomena, including cataract formation and erythrocyte senescence. Abnormal activation of the large stores of latent calpain in neurons induces cell injury and is believed to underlie neurodegeneration in excitotoxicity, Wallerian degeneration, and certain other neuropathologic states involving abnormal calcium influx. In Alzheimer's disease, we found the ratio of activated calpain I to its latent precursor isoform in neocortex to be threefold higher than that in normal individuals and those with Huntington's or Parkinson's disease. Immunoreactivity toward calpastatin, the endogenous inhibitor of calpain, was also markedly reduced in layers II-V of the neocortex in Alzheimer's disease. The excessive calpain system activation suggested by these findings represents a potential molecular basis for synaptic loss and neuronal cell death in the brain in Alzheimer's disease given the known destructive actions of calpain I and its preferential neuronal and synaptic localization. In surviving cells, persistent calpain activation may also contribute to neurofibrillary pathology and abnormal amyloid precursor protein trafficking/processing through its known actions on protein kinases and the membrane skeleton. The degree of abnormal calpain activation in the brain in Alzheimer's disease strongly correlated with the extent of decline in levels of secreted amyloid precursor protein in brain. Cytoskeletal proteins that are normally good calpain substrates become relatively calpain resistant when they are hyperphosphorylated, which may contribute to their accumulation in neurofibrillary tangles. As a major effector of calcium signals, calpain activity may mirror disturbances in calcium homeostasis and mediate important pathologic consequences of such disturbances
— id: 25180, year: 1994, vol: 747, page: 77, stat: Journal Article,