MICROGLIA IN ALS

Role of microglial cells during neurodegeneration in Amyotrophic Lateral Sclerosis

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 Obiettivo del progetto (Objective)

'Amyotrophic Lateral sclerosis (ALS) is an adult-onset neurodegenerative disease affecting motor neurons and leading to paralysis and death of the patients. Missense mutations in the gene for the ubiquitously expressed Cu/Zn superoxide dismutase (SOD1) are the best known cause for familial ALS leading to motor neuron death through an acquired toxic function still unidentified. Mice expressing ubiquitously mutant SOD1 develop ALS and although paralysis arises from death of motor neurons it is now clear that different, especially glial, cell types expressing mutant SOD1 contribute to the disease mechanism. Indeed, we have shown that microglial cells, the macrophage of the central nervous system, are implicated in the progression of the disease. Microglial cells originate from hematopoietic cells that colonize the CNS during development, have both neurotrophic and neurotoxic capabilities and are the first cell type to react to any kind of lesion in the CNS including familial and sporadic ALS. With this project I would like to go a step forward in understanding how microglial cells are implicated in motor neuron degeneration. Therefore, the objectives of this project are to study the interactions between macrophages/ microglial cells and motor neurons in ALS mouse models with the aim of increasing motor neuron survival and improving symptoms of the disease. In particular, we want to address (1) the mechanisms of microglial neurotoxicity, especially excitotoxicity, (2) the signals coming from motor neurons that could attract microglial cells and (3) the participation of the peripheral macrophages (macrophages in peripheral tissues and the ones infiltrating the CNS) to motor neuron degeneration in ALS models. As microglial cells are activated both in familial and sporadic ALS, these findings could provide a foundation for discovery of general pathways of motor neuron disease and open a way to identify new targets for development of therapies.'

Introduzione (Teaser)

A European study investigated the role of microglia, glial cells critical for immune response, on the progression of a rare neurodegenerative condition.

Descrizione progetto (Article)

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease of adulthood which leads to gradual paralysis and death within 5 years from onset. Currently, no treatment exists that can stop progressive motor neurodegeneration in these patients.

Accumulating evidence indicates that microglial cells, the macrophages of the central nervous system, are implicated in disease progression. Since ALS is diagnosed when symptoms are evident, the work of the EU-funded 'Role of microglial cells during neurodegeneration in amyotrophic lateral sclerosis' (MICROGLIA IN ALS) project focused on this phase of the disease.

The second most frequent form of familial ALS is associated with mutations in the superoxide dismutase (SOD1) enzyme. Scientists therefore used animal models with SOD1 mutations that best recapitulate disease symptoms to analyse the interaction between microglia and neurons. They investigated the role of a glutamate transporter (system xc-) expressed by microglia and found that it played a key role in microglial functions and ALS progression.

With respect to the attraction of microglial cells around affected motor neurons, scientists studied whether chemokines participated in the process. To distinguish the role of peripheral macrophages versus CNS microglia in motor neuron degeneration in ALS models, they employed a macrophage replacement approach.

Microglia activation is encountered in both familial and sporadic ALS. As such, the findings of the study lay the ground for discovering general pathways implicated in motor neuron disease. Importantly, exploitation of the generated information could help develop novel therapies for ALS.