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«TITLE: HEREDOATAXIAS: ANALYSIS OF MITOCHODRIAL DAMAGE AS AN UNITARY PATHOGENIC MODEL • Nombre y apellidos del investigador principal Adriano ...»

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CONVOCATORIA DE PROYECTOS DE INVESTIGACIÓN EN

NEUROCIENCIA-2014

Fundación Tatiana Pérez de Guzmán el Bueno

TÍTULO: HEREDOATAXIAS: ESTUDIO DE UN MODELO PATOGENICO COMUN

MEDIANTE ANALISIS DE FUNCION MITOCONDRIAL

TITLE: HEREDOATAXIAS: ANALYSIS OF MITOCHODRIAL DAMAGE AS AN

UNITARY PATHOGENIC MODEL

• Nombre y apellidos del investigador principal Adriano Jiménez Escrig, MD PhD (PI)

• Entidad solicitante Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS). Madrid, España.

• Situación laboral del investigador principal Facultativo Especialista Neurología en activo

• Datos de contacto del investigador principal Servicio de Neurología. Hospital Ramón y Cajal, Madrid Carretera de Colmenar Km 9. Madrid 28034, España

• Datos de contacto del responsable de la entidad solicitante José Ignacio Flores Nicolás Fundación para la Investigación Biomédica del Hospital Ramón y Cajal (FIBIO-HRyC).

Carretera de Colmenar Km 9. Madrid 28034, España

• Fecha y firmas del investigador principal y del responsable de la entidad ________________ _______________

A. Jiménez Escrig J.I. Flores Nicolás

CONVOCATORIA DE PROYECTOS DE INVESTIGACIÓN EN NEUROCIENCIA-2014. FUNDACION TATIANA

PEREZ DE GUZMAN EL BUENO

• Resumen del proyecto en español y en inglés

HEREDOATAXIAS: ESTUDIO DE UN MODELO PATOGENICO COMUN

MEDIANTE ANALISIS DE FUNCION MITOCONDRIAL

Fundamentos: Las hererdoataxias están constituidas por un alto número de enfermedades que difieren en el desorden genético que las origina aunque cursan con síntomas clínicos relacionados. En la mayoría de ellas, la alteración causante de la enfermedad determina una disfunción mitocondrial que afecta la homeostasis intracelular.

Objetivos: 1) Delimitar la alteración genética responsable de la ataxia en cada paciente. 2) Valorar las consecuencias de las diferentes alteraciones genéticas sobre la función mitocondrial en cada uno de los pacientes atáxicos estudiados.

Metodología: Se incluirán 48 pacientes con heredoataxias en los que se hará una evaluación genética exhaustiva mediante estudio de los 88 genes causantes de heredoataxias, con tecnología HaloPlex y secuenciación masiva de ADN mitocondrial en PGM-IonTorrent.

Posteriormente en estos pacientes se evaluarán las alteraciones mitocondriales (mitocondrias funcionales, mitocondrias totales, mitocondrias generadoras de ROS, mitofagia) y las señales indirectas de daño mitocondrial (formación de inflamasomas y actividad de caspasa-1).

Conclusión: Es un proyecto translacional en 2 fases, la primera traslada el desarrollo de las nuevas técnicas de secuenciación genómica a un grupo de pacientes necesitado de un estudio genético más amplio y la segunda fase valora los efectos de los genes mutados en una vía única que permita su uso como biomarcadores de severidad clínica y respuesta terapéutica.

HEREDOATAXIAS: ANALYSIS OF MITOCHODRIAL DAMAGE AS AN UNITARY

PATHOGENIC MODEL

Abstract Background: Heredoataxias are a group of different diseases caused by a number of gene mutations manifested by similar clinical symptoms. In most of them, the genetic disorder causes mitochondrial dysfunction that affects intracellular homeostasis.

Objectives: 1) To define the genetic causal mutation in a group of patients with heredoataxia and 2) to examine the mitochondrial dysfunction that cause the different mutations.

Methods: We plan to include 48 patients with heredoataxias that will undergo a thorough genetic evaluation by testing the 88 genes that are involved in heredoataxias with HaloPlex and mitochondrial DNA by next generation sequencing in a PGM-IonTorrent machine. Afterwards, we will examine in these patients mitochondrial disorders (functional mitochondria, total mitochondria and ROS generating mitochondria), and the indirect signs of mitochondrial damage (formation of inflamosomes and caspase-1 activity).

Conclusion: This is a translational project in 2 phases: the first one transfers the development of new genome sequencing techniques to a group of patients that need a broader genetic study and the second one studies the effects of the mutated genes in a common pathway that allow its use as biomarkers of severity and therapy response.

CONVOCATORIA DE PROYECTOS DE INVESTIGACIÓN EN NEUROCIENCIA-2014. FUNDACION TATIANA

PEREZ DE GUZMAN EL BUENO

• Subvención solicitada a la Fundación especificando los montos para cada concepto financiable (No deben consignarse gastos indirectos)

-DNA extraction cost (10 euros x 48 cases)

- Massive sequencing genes in dominant and recessive ataxias:

(€ 510 x 48 cases)

The entire draft sequencing of candidate genes includes generation of a 48 sample library, the

generation of 5 templates and one 318 Sequencing Chip price:





Preparation of 48 Libraries = € 13,790, € 287.3 / sample.

• Preparing Templates = € 2620, € 54.6 / sample • Preparation of sequencing: € 8,100; € 168.8 / sample (Total € 510.6 / sample).

- Cost of NGS of mitochondrial DNA: (186 € x 48 cases)

The entire mitochondrial DNA sequencing project, including the generation of 48 libraries,

generation of 2 Sequencing Templates and 4 Chips 316:

Preparation of 48 Libraries = € 5360, € 111.7 / sample.

• Preparing Templates = € 1128, 23.5 € / sample • Preparation of sequencing 2440 €, € 50.8 / total sample (€186 / sample).

-material and means for cultures

-Reagents and labware

-Antibodies

-Kits valuation of mitochondrial damage, apoptosis and glutathione........€ 8.000

-HPLC-Columns

-Overheads (publication, hardware, office, hiring of services, etc.)..........€ 6.000

- Registration, and travel to a specialty congress 2nd and 3rd year...........€ 5.000 TOTAL project cost

• Financiación actual del grupo (IP y, en su caso, otros investigadores), especificando título del proyecto y monto de la subvención.

Ninguna en la actualidad.

• Financiación solicitada a otros organismos pendiente de resolución, especificando título del proyecto y monto de la subvención.

Título del proyecto: Desarrollo de una plataforma de diagnóstico de las ataxias genéticas mediante secuenciación de nueva generación Monto de la Subvención: 50.472,00€ Organismo: Federación de Ataxias de España (FEDAES)

CONVOCATORIA DE PROYECTOS DE INVESTIGACIÓN EN NEUROCIENCIA-2014. FUNDACION TATIANA

PEREZ DE GUZMAN EL BUENO

MEMORIA CIENTÍFICA

- Antecedentes, estado actual del tema y planteamiento del proyecto (máximo 3 páginas) Ataxia derives from the Greek word taxis ‘order’ in our language, so literally means ‘messy’ and is a clinical symptom. For lack of knowledge about the disorder, the term ataxia is used as a synonymous in different diseases in which impairment in motor coordination is the main symptom. In light of current knowledge about this disorder, ataxia cannot be considered a single disease but a disorder that appears in a large number of different diseases, approximately 88.

This means that, in clinical practice, it is not correct to say that a particular patient "has an ataxia" as a disease, since ataxia is not a single disease. Thus, two patients with ataxia may have very different diseases i.e. a mitochondrial lesion in Friedreich's ataxia or a channelopathy in SCA6. It is therefore necessary to know the specific type of ataxia that has a patient. Therefore, the first step to assess any treatment, prognosis, etc for every patient with ataxia is to find the underlying genetic defect that causes it, something usually not done in a high percentage of patients with ataxia.

Ataxias are considered to have a prevalence of 60 cases per 100,000 inhabitants (ref. 1-2). Thus, in a hospital with an area of 500,000 people 300 cases are expected, although this figure can be

increased by frequent pilgrimage diagnosis of these patients. Ataxias can be classified as:

Nongenetic ataxias (infectious, demyelinating, toxic, metabolic, vascular, tumor, inflammatory and degenerative paraneoplastic), and genetic ataxias that can be recessive, dominant and mitochondrial According to recent reviews (ref. 3-6), there are 52 recessive genetic ataxias (64 genes reported) (Table 1 of Annexe) and at least 41 dominant genetic ataxias (24 genes reported) (Table 2 of Annexe). Therefore, when a patient asks if there is any treatment for its ataxia, the answer has to be, "when we know what type of ataxia you have we will be able to answer your question".

The clinical approach to these patients is to exclude acquired causes of ataxia by physical examination, basic laboratory tests and immunology and the study with brain MRI and neurophysiological tests. Once acquired forms have been ruled out, or if the medical history suggests a genetic ataxia begins a genetic study to determine which the causative genetic mutation is among all causes listed in Tables 1 and 2.

Until recently it was not possible to undergo a complete genetic study of ataxia because the costs and time for studying a large number of genes made it unfeasible in clinical practice.

Therefore, the genetic study was limited to examining the most common gene (frataxin, SCA1, 2, 3, 6, 7) which leads to more than 80% of cases with negative genetic studies (9-12).

Recently this has changed since the development of techniques for next-generation sequencing (NGS) that allow to sequence a high number of genes, even an entire genome at low cost and in a short time (see ref.13-14). Therefore, in this project we intend to set-up this technique to the study of patients with ataxia for a rapid and efficient genetic ataxia type.

Molecular Pathogenesis of genetic ataxias: mitochondrial function as the unitary model Cerebellar ataxias are caused by dysfunction of different pathways. The main routes are alterations in protein homeostasis, ion channel disorders, defects in DNA repair mechanisms and mitochondrial dysfunction. Given the evidence of mitochondrial involvement poliglutamine disorders, channelopathies, impaired DNA repair, etc..., mitochondrial function will be primary or secondary affected in most of the hereditary ataxias. Mitochondria are cellular organelles responsible for energy supply to cells, essential for the development of its activity. Although the main function of mitochondria is to synthesize ATP via oxidative phosphorylation, they also regulate Ca2 + homeostasis, heme biogenesis and formation of metalloproteins containing ironsulfur clusters. In addition to these metabolic roles, nowadays it is considered that mitochondria acts as potent damage sensor platforms for intracellular regulatory and effector signals in different biological processes such as apoptosis, necrosis and autophagy. In recent years has also been described that mitochondria coordinate the activation of innate immunity at different levels (15, 16). Currently, innate immunity is seen as an evolutionary conserved defense system in which an encoded receiver network identifies germline tissue changes and initiates an

CONVOCATORIA DE PROYECTOS DE INVESTIGACIÓN EN NEUROCIENCIA-2014. FUNDACION TATIANA

PEREZ DE GUZMAN EL BUENO

immune response to regulate tissue homeostasis. These receptors are not exclusive innate immune cells but they also are expressed in somatic cells and each cell line expresses its own pattern of receptors.

Alterations in the integrity of the mitochondrial outer membrane are crucial for the release of cytochrome C and the formation of apoptosomas, protein structures that initiate the activation of caspase-9. This protease is implicated in the onset of programmed cell death (apoptosis), a key process in tissue homeostasis (17). It has been recently described that mitochondria are the integrator of different signs of damage and transforms this information in the generation of reactive oxygen species (ROS) and other signals that are detected by intracellular receptors innate immunity activating inflamasomas (18,19). Inflammasomes are multiproteic structures similar to apoptosomas involved in the activation of another protease, caspase-1, an enzyme that processes precursors of IL-1beta and IL-18 to its biologically active form (20). Excessive generation of ROS may be a determinant of cell death by necrosis. Through autophagy, cell engulfs damaged mitochondria (mitophagy) limiting the excessive production of free radicals (ROS), and limiting intracellular damage. Thus, mitophagy processes downregulate NLRP3 inflammasome activation (16, 18). Although initially inflammasomes structures were described as related to infection and inflammation, various studies implicate caspase-1 in the processing of more than 50 different proteins. It is considered that NLRP3 inflamasomas are involved in regulation of glycolysis and lipogenesis, so could be regarded as regulatory structures of intracellular homeostasis.

According to the above mentioned data the mitochondria seems to be a key regulator to the decision to induce cell death or to initiate repairing mechanisms depending on the cell damage.



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