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Massimo Pregnolato


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Massimo Pregnolato

  1. 1. The Role of Microtubules in Psychopathology Massimo Pregnolato Dipartimento di Scienze del Farmaco Università degli Studi di Pavia (IT) Web : e-mail: "A Long Shadow over the Soul"Molecular and Quantum Approaches to Psychopathology An Interdisciplinary Dialog with Psychiatrists Fano. March, 31, 2012
  2. 2. Is it possible that psychopathological diseases such as depression (Cocchi, 2010) and psychosis (van Woerkom, 1990; Benitez-King, 2004) involve different states of consciousness (Morin, 2006) through the biological interface called: "Cytoskeletal Quantum Nanowire-Network"?
  3. 3. Quantum Cytoskeleton Nanowire NetworkMTs and Actin filaments can be viewed as computationally relevant nanowirenetworks that operate within neurons providing several functions among them theconnection of the cell nucleus with the postsynaptic density (Woolf, 2010).Potential computational modes for MTs and actin filaments are beginning to beunderstood, with two main quantum models for MT information processing havingbeen proposed.
  4. 4. The Penrose-Hameroff Orch OR model of consciousnessMicrotubules are protein polymers inside brain neurons proposed toact as quantum computersStuart Hameroff Roger Penrose
  5. 5. Tubulin Tubulin is a globular protein and the fundamental component of microtubules. Microtubules (MTs) constitute the cytoskeleton of all the eukaryotic cells and are supposed to be involved in many key cellular functions
  6. 6. Microtubules (MTs)Microtubules are cylindrical polymers composed by alpha and beta-tubulin dimers. MTs diameter is around 15 nm and their length canvary from a few nm up to some cm. MTs have optical, electrical and quantum properties that might explain long-distance intracellular communication processes
  7. 7. Excitation of vibration in microtubules in living cellsration in microtubules in living cells. Jiří Pokorný May 13, 2011 In recent years coherent excitations have been found in living cells emanating from microtubules at 8 Megahertz P Pokorný, J. (2004) Excitation of vibration in microtubules in living cells. Bioelectrochem. 63: 321-326.
  8. 8. Experimental and Computational Studies on Biophysical Properties of MicrotubulesResonance - Microtubules: sharp (0,30 Hz) peak of mechanical resonance at a frequency of 1510 MHz - Tubulin and control solution did not show any reaction MT molecular tubular structure can be responsible for the observed amplification of the signalBirefringence MTs react to electromagnetic fields in a different way than tubulin and control: birefringence effect is always higher in MTs than in tubulin and control, with statistical significance This suggests again that the molecular structure of MTs could be the cause of their reaction to electro-magnetic fieldsPizzi R, Strini G, Fiorentini S, Pappalardo V and Pregnolato.M Evidences Of New Biophysical Propertiesof Microtubules. Focus on Artificial Neural Networks cap. 9. pag. 191-207. Edited by John A. Flores. NovaScience Publisher Inc. 2011
  9. 9. Physico-Chemical Computational Simulation SONNIA (Self-Organizing Neural Network for Information Analysis) ITSOM (Inductive Tracing Self-Organizing Map) network MTs which in the dynamic evolution at zero field tend to move off their initial position, under the influence of the electric field tend to return to the starting position and to stabilize. MTs spatial organization is stronger than tubulin alone even in absence of field. The presence of electric field causes a decrease of conflicts, indicating a better structural organization, confirmed both by SONNIA and by the ITSOM attractors, that show a high regularity and compactness.Pizzi R, Fiorentini S, Strini G and Pregnolato M. Exploring Structural and Dynamical Properties ofMicrotubules by Means of Artificial Neural Networks. Complexity Science, Living Systems and ReflexingInterfaces: New Models and Perspectives. edited by Franco Orsucci and Nicoletta Sala. IGI Globalpublisher , 2012. in press.
  10. 10. 2007 - Schrodingers protein evidences (1)
  11. 11. 2010 - Schrodingers protein evidences (2)
  12. 12. 2010 - Schrodingers protein evidences (3)
  13. 13. Tubulin: a Scrodinger’s protein Tubulin exist in quantum superposition of different states and function like a quantum bit, or qubitHameroff, S, Penrose, R (1995) Orchestrated reduction of quantum coherence in brain microtubules: A model forconsciousness. Neural Network World, Vol. 5(5): 793-804.Hameroff, S (2007) Orchestrated Reduction of Quantum Coherence in Brain Microtubules. NeuroQuantology. 5 (1) 1–8.)
  14. 14. Penrose observed that quantum superposition – an object in two places/states simultaneously – equated to two spacetime curvatures in different directions: a bubble or separation in the fabric of realityBut the separations are unstable, and after a time t (given by E=h/t) will spontaneouslyself-collapse to one curvature or the other (an “objective reduction” – O.R.).
  15. 15. The Penrose-Hameroff model suppose that quantum-superposed states developin tubulins, remain coherent and recruit more superposed tubulins until a mass-time-energy threshold, related to quantum gravity, is reached (up to 500 msec).This model predicts dendritic webs of approximately 100,000 neurons for discreteconscious moments, or frames, occurring every 25 ms in gamma synchrony. Bing
  16. 16. Interior schematic of dendrites in quantum isolation phase. Actin haspolymerized into gel form and MAPs detached, shielding and isolating MTswhose tubulins have evolved into quantum superposition
  17. 17. Molecular simulation of tubulin with Schematic tubulin with non-beta tubulin (dark gray) on top and polar hydrophobic phenyl ringsalpha tubulin (light gray) on bottom. approximating actually phenylNon-polar amino acids phenylalanine and indole rings. Scale bar: 1and tryptophan with aromatic phenyl nanometer.and indole rings are shown.(Travis Craddock and Jack Tuszynski)
  18. 18. 2011 - Hameroff-Penrose Theory UpdatesFour versions of the schematic Orch OR tubulin bit (superpositioned qubit states not shown).•Early version showing conformational change coupled to/driven by single hydrophobicpocket with two aromatic rings.•Updated version with single hydrophobic pocket composed of 4 aromatic rings.•McKemmish (2009) mis-characterization of Orch OR tubulin bit as irreversibleconformational change driven by GTP hydrolysis.•Current version of Orch OR bit with no significant conformational change (change occurs atthe level of atomic nuclei) and multiple hydrophobic pockets arranged in channels.
  19. 19. 2011 - Direct Experimental Evidence for the Quantum States in Microtubules and Topological Invariance Series of coherence resonance peaks in single microtubules ranging from 12 kilohertz to 8 megahertz. Anirban Bandyopadhyay National Institute of Material Sciences in Tsukuba, JapanUsing nanotechnology they interface via AFM/STM electrodes to opposite ends of a single viablemicrotubule (MT). They vary AC and DC conditions and study electronic transport properties attemperatures ranging from 10K to room temperature. At specific conditions they found:3)spontaneous MT growth leading to Frohlich condensation4)ballistic electronic transport,5)ferroelectric MT properties.•Multilevel information processing and memory (beyond binary logic) in MT•Efforts to understand room temperature coherent transport in terms of band energies.•Challenges and resolution of detection of MT topological quantum bits, or qubits based onHemchandra/Fibonacci MT geometry at physiological temperature.Bandyopadhyay A (2011) Direct experimental evidence for quantum states inmicrotubules and topological invariance. Abstracts: Toward a Science of Consciousness2011, Sockholm, Sweden,
  20. 20. Extending microtubule A-lattice hydrophobic channels results in helical winding patterns matching Fibonacci geometry.Bandyopadhyay (2011) has evidence for ballistic conductance and quantuminteference along such helical pathways which may be involved in topologicalquantum computing. Quantum electronic states of London forces in hydrophobicchannels result in slight superposition separation of atomic nuclei, sufficient EG forOrch OR. This image may be taken to represent superposition of four possibletopological qubits which, after time T=tau, will undergo OR, and reduce tospecific pathway(s) which then implement function.Roger Penrose, and S. Hameroff. Consciousness in the Universe: Neuroscience, Quantum Space-TimeGeometry & Orch OR Theory. Journal of Cosmology Volume 14 Consciousness and the Universe. 2011
  21. 21. Summary of Bandyopadhyay results (2011)1) Microtubules have 8 resonance peaks for AC stimulation (kilohertz to 10 megahertz) which appear to correlate with various helical conductance pathways around the geometric microtubule lattice.2) Excitation at these resonant frequencies causes microtubules to assemble extremely rapidly, possibly due to Fröhlich condensation.3) In assembled microtubules AC excitation at resonant frequencies causes electronic conductance to become lossless, or ballistic, essentially quantum conductance, presumably along these helical quantum channels. Resonance in the range of kilohertz demonstrates microtubule decoherence times of at least 0.1 millisecond.4) Eight distinct quantum interference patterns from a single microtubule, each correlating with one of the 8 resonance frequencies and pathways.5) Ferroelectric hysteresis demonstrates memory capacity in microtubules.6) Temperature-independent conductance also suggests quantum effects.If confirmed, such findings would demonstrate Orch OR to be biologically feasible!
  22. 22. The Craddock and Tuszynski modelDescribe classical and quantum informationprocessing in MTs based on a double-well potentialin the interior of the tubulin dimer.Mapping electrostatic partial charges in the interiorof tubulin dimer shows a region in the alphamonomer near the neck to the beta monomer of twoareas of positive charge in the range of 100-150meV. Electrostatic map of a horizontal slice through tubulin near the “neck” between the alpha and beta monomers shows a “double well” of positive charge.Craddock TJA, Beauchemin C, Tuszynski JA. Information processing mechanisms in microtubules atphysiological temperature: Model predictions for experimental tests. Biosystems 2009; 97: 28-34.Craddock TJA, Tuszynski JA. A critical assessment of the information processing capabilities ofneuronal microtubules using coherent excitations. J Biol Phys 2010; 36: 53-70.
  23. 23. The best correlate of consciousness(NCC) comes from EEG,EEG is divided intofrequency bands:Delta (< 4 Hz)Theta (4 to 8 Hz)Alpha (8 to 12 Hz)Beta (13 to 30 Hz)Gamma (> 30 Hz)Coherence in gamma synchronyamong different brain regions isthe best correlate of consciousness
  24. 24. The conscious pilotRefers to spatiotemporal envelopes of dendritic gamma synchrony (demarcated by gap-junction-defined “dendritic webs”) moving through the brain as vehicle for a consciousagent which can experience and control otherwise non-conscious (autopilot) cognitivefunctions. The best measurable “neural correlate of consciousness” (NCC), is gammasynchrony EEG, coherent field potential oscillations in the range from 30 to 90 Hz(prototypical 40 Hertz). Gamma synchrony, along with consciousness, apparently movesand evolves through various global distributions and brain regions (Hameroff, 2010).
  25. 25. I Networks Sensory-driven e Default Mode• Percezioni sensoriali• Controllo del comportamento• Apprendimento, Memoria• Attenzione, Sonno• Linguaggio• Intelligenza• Viscerale/sessuale possono essere NON CONSCI Chalmers’ easy problems Zombie Auto-pilot
  26. 26. • Percezione sensoriale• Comportamento• Apprendimento• Memoria Bing• Attentione, Sonno• Linguaggio• Intelligenza Bing• Viscerale, Sessuale Bing …o CONSCI
  27. 27. •Percezione sensoriale• Comportamento• Apprendimento•Memoria Bing• Attenzione, Sonno Bing• Linguaggio• Intelligenza• Viscerale, Sessuale Bing muovendosi e ridistribuendosi nel cervello
  28. 28. • Percezione sensoriale• Comportamento Bing• Apprendimento, Memoria Bing• Attenzione• Linguaggio• Intelligenza Bing• Viscerale, Sessuale muovendosi e ridistribuendosi nel cervello
  29. 29. • Percezioni sensoriali Bing• Conportamento• Apprendimento, Memoria• Attenzione• Linguaggio Bing• Intelligenza• Viscerale, Sessuale Bing muovendosi e ridistribuendosi nel cervello La coscienza si muove attraverso le aree del cervello in zone di sincronia gamma!
  30. 30. The above-described coherent framework reflects the meaning of theability of a quantitative approach to psychopathology.Is there any correlation between hallucination and cell-molecularinteractions, or any cause for changing the conscious state that may bedetected by measuring the gamma synchrony, which is bettercorrelated to consciousness and which has already provided avariability of responses in different psychopathological conditions andmeditation?Flynn G, Alexander D, Harris A, Whitford T, Wong W, Galletly C, Silverstein S, Gordon E, WilliamsLM. Increased absolute magnitude of gamma synchrony in first-episode psychosis.Schizophr Res. 2008 Oct;105(1-3):262-71.
  31. 31. EcstasyNeuro Correlate of Consciousness Hyper alert Levels of Ordinary State of (i.e. Gamma Synchrony ?) Stupor Pure biological level Consciousness Bio-eco-logical level Mnemonic extended level Identity level Mystery level of the ego Lethargic Anesthesia Coma Unconsciousness
  32. 32. The role of microtubules in psychopathologyAccording to Woolf et al. MTs dysfunction occurring in mental illness might be expected tocause abnormal tubulin oscillations between polymerization-depolymerization cycles resultingin different arrays mixtures (classified by Craddock as types I–IV behaviors).Depression could results from too little type IV behavior which is associated with informationprocessing systems. Billions of quantum computations in MTs would be responsible for movingmillions of proteins over nanometer distances, with the most salient among the collectiveeffects affecting neural activity on millisecond time scales.Woolf concluded that: “….classical and quantum information processing in brain MTs could beimpaired in mental illness, to the extent that such information processing modes are validatedby experimental support”.Woolf N, Craddock T, Friesen D, Tuszynski J. Neuropsychiatric illness: a case for impaired neuroplasticityand possible quantum processing derailment in microtubules. NeuroQuantology 2010; 8(1): 13-28.
  33. 33. Major depressive disorderMajor depressive disorder (alsoknown as recurrent depressivedisorder, clinical depression, majordepression, unipolar depression, orunipolar disorder) is a mental disordercharacterized by an all-encompassinglow mood accompanied by low self-esteem, and by loss of interest orpleasure in normally enjoyableactivities.The diagnosis of major depressivedisorder is based on the patients self-reported experiences, behaviorreported by relatives or friends, and amental status exam. There is nolaboratory test for major depression,although physicians generally requesttests for physical conditions that maycause similar symptoms. Vincent van Goghs 1890 painting At Eternitys Gate
  34. 34. Ipotesi molecolare della Depressione Acido Arachidonico, Fluidità di Membrana e SerotoninaCocchi et al hanno tentato di spiegare il possibile ruolo della fluidità dellamembrana delle piastrine nella modulazione dei livelli di serotonina nelcervello, con un processo che coinvolge l’acido arachidonico (AA).In questi lavori è stata dimostrata l‘importanza di tre acidi grassi nei fosfolipididella membrana delle piastrine di sangue prelevato a pazienti depressi. Acido Palmitico (PA) Acido linoleico (LA) Acido Arachidonico (AA) Massimo Cocchi (2008)
  35. 35. La membrana piastrinica delle persone depresse è caratterizzata daun grado più elevato di insaturazioni rispetto al gruppo di soggetticlinicamente sani ed è emersa una correlazione diretta tra laconcentrazione di Acido Arachidonico nelle piastrine e nei neuroni eduna correlazione inversa con la concentrazione di serotonina. Kary Mullis (Nobel Prize 1993) said: “It is a very important discovery. Just think that, through this method it will be possible to understand if a patient will have intention to commit suicide. It is a philosophic, medical and religious revolution.” (Il Resto del Carlino, May 28, 2008). 39
  36. 36. Lipid rafts are specialised structures on the plasma membrane that have analtered lipid composition as well as links to the cytoskeleton. S-Palmitoylation isthe covalent attachment of fatty acids, such as palmitic acid, to cysteine residuesof membrane proteins including Gsα.Il gruppo di ricerca di Rasenick che studia laproteina Gsα nei neuroni di suicidi,ha evidenziato i microdomini lipidici raft dellamembrana quali elementi critici divulnerabilità dei neuroni nelladepressione. Recenti scoperte mostrano cheun circuito molecolare, a partire dallaviscosità della membrana, può modulare lacascata di segnalazione che coinvolge leproteine Gsα e la tubulina.
  37. 37. Post-synaptic Density Interactome Interactome is defined “as the whole molecular interactions that take place in an organism and allow the cascade of regulatory molecules including the mechanism of action of enzymes and metabolic reactions”. The interactions between different proteins are in fact the basic physiological mechanisms that regulate and monitor the performance of all bodily functions. Protein interaction network decomposition reveals functional modules and motifs. (Rual et al, 2005, Towards a proteome-scale map of the human protein–protein interaction network, Nature, 437: 1173-1178.)Recent data estimate approximately 650,000 human interactions between proteinsStumpf MPH, Thorne T, de Silva E, Stewart R, Hyeong JA, Lappe M, Wiuf C. Estimating the size of the human interactome.PNAS 2008; 105: 6959-6964
  38. 38. Protein- Protein Interaction
  39. 39. L’interazione Gsα – TubulinLa principale interazione proteica da prendere in considerazione nella densitàpost-sinaptica dell’interattoma, è linterazione Gsα-tubulina. L’aumento dellaGsα catalizza la polimerizzazione dei MTs. Nella Depressione Maggiore ladiminuzione dellinterazione Gsα – Tubulina causa una riduzione del networkcitoscheletrico e dei fenomeni quantistici molecolari implicati negli stati dicoscienza.Layden BT, Saengsawang W, Donati RJ, Yang S, Mulhearn DC, Johnson ME, Rasenick MM.Structural model of a complex between the heterotrimeric G protein, Gsalpha, and tubulin. BiochimBiophys Acta. 2008; Jun;1783(6):964-73.Gsα Giα
  40. 40. Gli antidepressivi e gli antipsicotici mostrano il loro effetto terapeutico conuna latenza di 2-6 settimane. Il fatto che la prima parte di questo periodo(2 settimane) corrisponda al tempo di riorganizzazione del citoscheletroneuronale suggerisce che gli agenti psicofarmacologici possono esplicare iloro effetti clinici attraverso lalterazione del citoscheletro.Woolf N, Craddock T, Friesen D, Tuszynski J. Neuropsychiatric illness: a case for impairedneuroplasticity and possible quantum processing derailment in microtubules. NeuroQuantology2010; 8(1): 13-28.
  41. 41. 3 1 2
  42. 42. Alzheimer’s Disease•Alzheimer’s disease (AD) is a prevalentneurodegenerative disorder, and the majorcause of dementia in the elderly.•Early symptoms, including inability to formnew memories, confusion, and moodswings, can lead to loss of language, long-term memory, bodily functions, and death.•Although numerous therapeuticapproaches have been implemented, nosignificantly useful treatments or cures areavailable, other than recommendations toexercise one’s mental facilities.•With tens of millions of AD patientsworldwide requiring care, and more andmore reaching mid-60’s and older ageswhen AD usually strikes, the diseasepresents global medical, social andeconomic problems of enormous proportion.
  43. 43. The brains of AD patients have three types of neuropathological lesions:3)Extracellularly, excessive accumulation of the ∼4 kD peptide, known as Aβ,derived from the β-amyloid precursor protein (APP), leads to amyloid (senile)plaques and oligomers associated with impairment of LTP and synapticfunction4)At the intracellular level, cortical neurons in the AD brain accumulate hyper-phosphorylated tau, a MAP, which triggers the formation of neurofibrillarytangles (NFTs).5)Neurons in AD brain demonstrate impaired axonal transport, motor proteintransport along axonal MTs, and compromised MT networks.Woolf suggested an imbalance of MAPs throughout brain neurons lead tocytoskeletal breakdown in ADR.E. Tanzi and L. Bertram. Twenty years of the Alzheimers disease amyloid hypothesis: A genetic perspective. Cell,120(4):545–555, 2005.A.D. Cash, G. Aliev, S.L. Siedlak, A. Nunomura, H. Fujioka, X. Zhu, A.K. Raina, H.V. Vinters, M. Tabaton, A.B.Johnson, M. Paula-Barbosa, J. Avla, P.K. Jones, R.J. Castellani, M.A. Smith, and G. Perry. Microtubule reduction inAlzheimer’s disease and aging is independent of tau filament formation. Am J Pathol, 162(5):1623–1627, 2003.N.J.Woolf, A. Priel, and J.A. Tuszynski. Nanotechnology, nanostructure, and nervous system disorders. InNanoneuroscience: Structural and Functional Roles of the Neuronal Cytoskeleton in Health and Disease, pages 177–226. Springer, Berlin; Heidelberg; New York, 2010.
  44. 44. Transcranial ultrasound (TUS)TUS application of mechanical vibrations to the scalp, e.g. in the temporal region, inthe range between 20,000 Hz and 30 megahertz, shown to have electrophysiologicaland behavioral effects in animals. Microtubules have been shown to haveresonances precisely in the range of TUS (e.g. 8 MHz).Thus, TUS may promote microtubule activity, and is a potential therapeutic tool forthe treatment of AD.Stabilization of the MT cytoskeleton by drug induced redistribution of zinc, or viaultrasonic techniques may not only prevent tauopathy and NFT formation, but, in amore general context, also ameliorate cognition based on the proposed role MTs ininformation processing.
  45. 45. Along with actin filaments and other cytoskeletal components, MTs grow, reshapeand modify neurons and synapses.Generally considered as merely cytoskeletal structural support, MTs have beenproposed to also function as intra-cellular information processing devices in whichsubunit states represent and process fundamental information bits. Y. Tufail, A. Matyushov, N. Baldwin, M.L. Tauchmann, J. Georges, and et al. Transcranial pulsed ultrasound stimulatesintact brain circuits. Neuron, 66:681–694, 2010.S.S. Yoo, A. Bystritsky, J.H. Lee, Y. Zhang, K. Fischer, and et. al. Focused ultrasound modulates region-specific brainactivity. Neuroimage, 56:1267– 1275, 2011.
  46. 46. CONCLUSIONIt seems to be consistent the hypothesis that Schrödinger proteinsinteractoma and in particular the cytoskeleton nanowire network isthe best biological interface for potential expression ofconsciousness, being typical and specific for each animal speciesand that consciousness is always a potential. It’s very fascinating tothink that every animal possess a primary Schrödinger proteinscomplex (cytoskeleton) and even in the absence of circulatingserotonin there is a potential of consciousness that is essential tothe behavior of some life forms, while other species such asinvertebrates, procariotes and even archea possess expertise intheir own domain probably mediated by their own Schrödingerproteins interactoma.
  47. 47. A great leader should mix Science & Art, Public & Private, Politics & Religions and think that this is the Creativity of Life. (Massimo Pregnolato) ThanksMassimo Cocchi, Lucio Tonello , Fabio Gabrielli, Stuart Hameroff, Mark Rasenick, Jack Tuszynski, Travis Craddock, Eliano Pessa, Paola Zizzi, Donald Mender