ALZHEIMER’S AND PARKINSON’S DISEASES FROM A PRIONOIDE PERSPECTIVE: ROLE OF NEURAL CONNECTIONS IN HUMANS AND TRANSGENIC MODELS (Q3137843)
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Project Q3137843 in Spain
| Language | Label | Description | Also known as |
|---|---|---|---|
| English | ALZHEIMER’S AND PARKINSON’S DISEASES FROM A PRIONOIDE PERSPECTIVE: ROLE OF NEURAL CONNECTIONS IN HUMANS AND TRANSGENIC MODELS |
Project Q3137843 in Spain |
Statements
77,440.0 Euro
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96,800.0 Euro
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80.0 percent
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1 January 2015
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31 December 2016
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UNIVERSIDAD DE CASTILLA-LA MANCHA
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38°57'35.10"N, 3°52'58.26"W
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13034
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LAS ENFERMEDADES DE ALZHEIMER (EA) Y PARKINSON (EP) SON LOS TRASTORNOS NEURODEGENERATIVOS DE MAYOR PREVALENCIA AUMENTANDO EXPONENCIALMENTE CON LA EDAD. AMBAS ENFERMEDADES SON IDIOPATICAS Y EL TRATAMIENTO TRADICIONAL HA SIDO PALIATIVO Y DIRIGIDO HACIA LOS RESPECTIVOS DEFICITS COGNITIVOS Y MOTORES QUE ACARREAN. NEUROPATOLOGICAMENTE, SON PROTEINOPATIAS EN LAS QUE SE GENERAN AGREGADOS (PLACAS DE BETA-AMILOIDE Y OVILLOS NEUROFIBRILARES DE TAU EN EA Y CUERPOS DE LEWY A PARTIR DE UBIQUITINA Y ALFA-SINUCLEINA EN EP). ESTOS DEPOSITOS APARECEN DE FORMA TEMPORAL Y PREDECIBLE, EN DISTINTAS ZONAS DEL SISTEMA NERVIOSO, DE ACUERDO A UNA SECUENCIA NEUROPATOLOGICA DE SEIS ESTADIOS. ULTIMAMENTE SE HAN IDO ACUMULANDO DATOS QUE APUNTAN A UN CAMBIO DE PARADIGMA EN EL ABORDAJE DE ESTAS PATOLOGIAS. ESTOS DATOS EVIDENCIAN LA EXISTENCIA DE UNA FASE PRECLINICA QUE COMENZARIA AÑOS E INCLUSO DECADAS ANTES QUE LOS SINTOMAS LLEVEN AL DIAGNOSTICO NEUROLOGICO. ES ESENCIAL CARACTERIZAR ESTA FASE PREDIAGNOSTICA PARA BUSCAR ESTRATEGIAS TERAPEUTICAS ANTES QUE EL PROCESO NEURODEGENERATIVO SEA IRREVERSIBLE. ESTE PERIODO ESTARIA CARACTERIZADO POR SINTOMAS TEMPRANOS ENTRE LOS QUE DESTACA LA PERDIDA DE OLFACCION. CURIOSAMENTE, LOS PRIMEROS DEPOSITOS NEUROPATOLOGICOS SE PRODUCEN EN ESTRUCTURAS DEL SISTEMA OLFATIVO. EN RELACION A ESTE NUEVO PARADIGMA, SE HA PROPUESTO UNA HIPOTESIS SEGUN LA CUAL ESTAS PROTEINOPATIAS SE EXTENDERIAN A LO LARGO DE LAS CONEXIONES DEL SISTEMA NERVIOSO MEDIANTE UN MECANISMO PRIONOIDE EN EL QUE UNA PROTEINA MAL PLEGADA TENDRIA LA CAPACIDAD DE INDUCIR A LAS PROTEINAS NATIVAS BIEN CONFORMADAS ESE PLEGAMIENTO ANOMALO E INDUCIR SU TRANSMISIBILIDAD MEDIANTE UNA REACCION DE CRISTALIZACION EN CADENA. EL PRESENTE PROYECTO TRATA DE TESTAR ESTA HIPOTESIS PRIONOIDE EN EL SISTEMA OLFATIVO DE CEREBROS DE PACIENTES DIAGNOSTICADOS CON LAS EA Y EP Y EN MODELOS TRANSGENICOS DE DICHAS ENFERMEDADES. SE PROPONEN CUATRO OBJETIVOS ESPECIFICOS: _x000D_ 1. ANALIZAR LA DISTRIBUCION TEMPORAL DE BETA-AMILOIDE Y TAU EN EL SISTEMA OLFATIVO HUMANO DE CEREBROS DE PACIENTES DIAGNOSTICADOS CON EA (ESTADIOS III-VI) Y CONTROLES Y LA VULNERABILIDAD DE DISTINTAS SUBPOBLACIONES NEURONALES A ESTA PROTEINOPATIA._x000D_ 2. ANALIZAR LA DISTRIBUCION TEMPORAL DE AGREGADOS DE ALFA-SINUCLEINA EN EL SISTEMA OLFATIVO HUMANO DE CEREBROS DE PACIENTES DIAGNOSTICADOS CON EP (ESTADIOS III-VI) Y CONTROLES Y LA VULNERABILIDAD DE DISTINTAS SUBPOBLACIONES NEURONALES A ESTA PROTEINOPATIA. _x000D_ 3. VALORAR LA TRANSMISIBILIDAD ANTEROGRADA Y/O RETROGRADA DE BETA-AMILOIDE Y TAU EXOGENOS INOCULADOS EN EL BULBO Y LA CORTEZA OLFATIVA DE RATONES PS1XAPP MODELOS DE LA EA Y CONTROLES A LOS 4 Y 8 MESES POSTINYECCION, HASTA LA CORTEZA ENTORRINAL, REALIZANDO UNA CORRELACION CON TRAZADORES._x000D_ 4. VALORAR LA TRANSMISIBILIDAD ANTEROGRADA Y/O RETROGRADA DE AGREGADOS DE ALFA-SINUCLEINA EXOGENA INOCULADA EN EL BULBO Y LA AMIGDALA DE RATONES A53T MODELOS DE LA EP Y CONTROLES A LOS 4 Y 8 MESES POSTINYECCION, HASTA LA SUSTANCIA NEGRA, REALIZANDO UNA CORRELACION CON TRAZADORES._x000D_ LOS RESULTADOS ESPERADOS INCLUIRIAN LA CARACTERIZACION DETALLADA DE LA EXPRESION BETA-AMILOIDE, TAU Y ALFA-SINUCLEINA, LA MUERTE NEURONAL ASOCIDA Y DE LA VULNERABILIDAD PREFERENCIAL DE CIERTAS SUBPOBLACIONES DE INTERNEURONAS EN EL SISTEMA OLFATIVO HUMANO. (Spanish)
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ALZHEIMER’S (AD) AND PARKINSON’S (EP) DISEASES ARE THE MOST PREVALENT NEURODEGENERATIVE DISORDERS INCREASING EXPONENTIALLY WITH AGE. BOTH DISEASES ARE IDIOPATICS AND THE TRADITIONAL TREATMENT HAS BEEN PALLIATIVE AND DIRECTED TOWARDS THE RESPECTIVE COGNITIVE DEFICITS AND MOTORS THEY CARRY. NEUROPATOLOGICAL ARE PROTEINOPATIAS IN WHICH AGGREGATES ARE GENERATED (BETA-AMYLOID PLATES AND TAU NEUROFIBRILLARY BALLS IN EA AND LEWY BODIES FROM UBIQUITIN AND ALPHA-SINUCLEIN IN EP). THESE DEPOSITS APPEAR TEMPORARILY AND PREDICTABLY, IN DIFFERENT AREAS OF THE NERVOUS SYSTEM, ACCORDING TO A SIX-STAGE NEUROPATOLOGICAL SEQUENCE. LATELY, DATA HAVE BEEN ACCUMULATED THAT POINT TO A PARADIGM SHIFT IN THE APPROACH TO THESE PATHOLOGIES. THESE DATA SHOW THE EXISTENCE OF A PRECLINIC PHASE THAT WOULD BEGIN YEARS AND EVEN DECADES BEFORE THE SYMPTOMS LEAD TO NEUROLOGIC DIAGNOSIS. IT IS ESSENTIAL TO CHARACTERISE THIS PREDIAGNOSTICAL PHASE TO SEEK THERAPEUTIC STRATEGIES BEFORE THE NEURODEGENERATIVE PROCESS IS IRREVERSIBLE. THIS PERIOD WOULD BE CHARACTERISED BY EARLY SYMPTOMS AMONG WHICH THE LOSS OF OLFACTION STANDS OUT. INTERESTINGLY, THE FIRST NEUROPATOLOGICAL DEPOSITS OCCUR IN STRUCTURES OF THE OLFACTORY SYSTEM. IN RELATION TO THIS NEW PARADIGM, A HYPOTHESIS HAS BEEN PROPOSED ACCORDING TO WHICH THESE PROTEINOPATIAS ARE EXTENDED ALONG THE CONNECTIONS OF THE NERVOUS SYSTEM THROUGH A PRIONOIDE MECHANISM IN WHICH A POORLY FOLDED PROTEIN WOULD HAVE THE ABILITY TO INDUCE THE WELL-FORMED NATIVE PROTEINS THAT ANOMALY FOLDED AND INDUCE ITS TRANSMISSIBILITY THROUGH A CHAIN CRYSTALLISATION REACTION. THIS PROJECT SEEKS TO TEST THIS PRIONOIDE HYPOTHESIS IN THE BRAIN OLFACTORY SYSTEM OF PATIENTS DIAGNOSED WITH AD AND PE AND IN TRANSGENIC MODELS OF THESE DISEASES. FOUR SPECIFIC OBJECTIVES ARE PROPOSED: _x000D_ 1. Analyse THE TEMPORAL DISTRIBUTION OF BETA-AMILOIDE AND TAU IN THE HUMAN OLFATIVAL SYSTEM OF PACIENT CREBRES DIAGNOSTICED WITH EA (ESTADIOS III-VI) AND CONTROLS AND VULNERABILITY OF DYSTINE SUBPOBLACIONS NEURONAL TO THIS PROTEINOPATIA._x000D_ 2. ANALYSE THE TEMPORAL DISTRIBUTION OF ALPHA-SINUCLEIN AGGREGATES IN THE HUMAN OLFACTORY SYSTEM OF BRAINS OF PATIENTS DIAGNOSED WITH PE (STAGES III-VI) AND CONTROLS AND THE VULNERABILITY OF DIFFERENT NEURAL SUBPOPULATIONS TO THIS PROTEINOPATIA. _x000D_ 3. Assess the transmissibility of BETA-AMILOIDE AND TAU EXOGENES inoculated in the BULB AND the OLFATIVE CORTEZA OF RATONS PS1XAPP models of the EA and control at 4 and 8 months postinjection, BUT THE ENTORRINAL CORTEZA, performing a correlation with TRAZATORS._x000D_ 4. Assess the previous transmissibility AND/or retrograde of ALFA-synuclein AGREGATE EXOGINE inoculated in the BULB AND AMIGDALA DE RATONES A53T models of the EP and control them at 4 and 8 months POSTINYECTION, HAS the NEGRA SUSTANCE, performing a correlation with TRAZATORS._x000D_ SPERED RESULTS would include the detailed CHARACTERISATION OF BETA-AMILOID EXPRESSION, TAU AND ALFA-sinuclein, the NEURONAL DEATH ASSOCED AND THE VULNERABILITY PREFERENTIAL OF CIERTS SUBPOBLACIONS OF INTERNEURONAS IN THE HUMAN OLFATIVO SYSTEM. (English)
12 October 2021
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Ciudad Real
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Identifiers
SAF2014-52300-R
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