RICERCA ITALIANA     

RELATIONSHIP BETWEEN MEMBRANE IONIC PERMEABILITY AND INTRACELLULAR RED-OX STATE DURING NEURODEGENERATIVE PROCESS: ACTION OF AMYLOID PEPTIDES IN NEURONAL AND GLIAL CELLS.

Università degli Studi di Roma "La Sapienza"

Abstract

One of the major apprehensions of contemporary society is population aging. Paradoxically, scientific discoveries that have significantly increased the life expectation have also created new medical problems, once sporadic, but now common in a growing number of aging individuals. Neurodegenerative diseases play a predominant role in this new scenario. There is significant evidence that the generation of reactive oxygen species (ROS) and mitochondrial dysfunction may be at the basis of several neurodegenerative diseases including Alzheimer's disease, Creutzfeldt-Jakobs prion disease, and polyglutamine-expansion diseases like Huntington. During aging, a decline in the cellular antioxidant defense system, can determine an unbalanced ROS activity leading to the destruction of cellular components including lipids, protein, and DNA, and ultimately to cell death via apoptosis or necrosis. Although numerous studies examined the role of increased ROS production in late-onset neurodegenerative disorders, the mechanisms by which neurons die under conditions of oxidative stress remain largely unknown. One of the causes of cytoplasmic oxidation in the central nervous system (CNS) cells is the assembly by neuron and glia cells of aberrant polypeptides species. One of the main features that several neurodegenerative disorders share is the deposition of protein aggregates, known as amyloid, which can be found extracellularly or, intracellularly in the cytoplasm or in the nucleus. In neurons >>>

Principal Investigator

Michele MAZZANTI Università degli Studi di ROMA "La Sapienza"

Research Objectives

Neurodegenerative disorders, including Alzheimer's (AD), prion protein diseases (PPD) and polyglutamine-expansion diseases (polyQD), share in common the occurrence of protein aggregates in ordered fibrillar structures, known as amyloid deposits, found extracellularly or intracellularly, in the cytoplasm or in the nucleus. The interaction of these aggregating polypeptides with the cells of the central nervous system (CNS), leading to neuronal death and glial cells activation, is still mainly obscure. The principal aim of our project is to determine a related mechanism of action of three different amyloid peptides in relation with their ability to modulate membranes ionic permeability.
By combining the scientific competences of the single research units we will be able to give and interdisciplinary approach to the scientific subject of the research program. Using physiological, morphological, biochemical and molecular experimental techniques we will explore the various aspects of amyloid peptides interaction with cells of the CNS. Secondarily, our confine geographic locations will guarantee a continuous direct contact between the three labs. This is of fundamental importance in a project deeply involving different expertise and different appropriated environments to perform the experiments. At last we will have the technical support of the research laboratories of Pirelli Labs, directed by Ing. Fontana, that are particularly skilled in electronics and optical >>>

Timescale

24 months

National and international background

One of the main features that many neurodegenerative disorders share is the deposition of insoluble protein aggregates, known as amyloids. In Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), prion protein diseases (PPD) such as the Creutzfeldt-Jakobs disease (CJD), and polyglutamine (polyQ) expansion diseases such as the Huntington disease (HD) and Spinocerebellar Ataxia type 1 (SCA1), the brain is characterized by the presence of senile plaques, deposits of abundant extracellular and intracellular insoluble amyloid, accompanied by selective neuronal loss (1). Amyloids are generated in a disease-specific manner from structurally unrelated proteins (2). AD is characterized by a progressive deposition of beta-amyloid (AB) fibrils in the brain to form senile plaques (3). The amyloidogenic material is mainly composed of beta-amyloid peptides that are proteolytically derived from a membrane precursor protein (4). The plaques are associated with reactive microglia and astrocytes as well as dystrophic neurites (5-6). PPD disorders are a family of neurodegenerative diseases characterized by the accumulation of a pathological form of the prion protein (PrPsc; 7). PrPsc is characterized by infectious nature, partial resistance to proteolysis, and capacity to aggregate extracellularly in the brain and to deposit as amyloid plaques in a subset of prion disorders (7-9). Plaque formation is correlated with the appearance of reactive astrocytes and >>>