Expanding Perspectives in Neurodegeneration: Considering Non-Neuronal Cells

Conférence du Centre de recherche CERVO
Date & Time: 
Friday, May 3, 2024 - 11:00
Speaker: 
Serge Przedborski
Affiliation: 

Page and William Black Professor of Neurology, Pathology & Cell Biology and Neuroscience
Vice-Chair of Research, Chief of the Movement Disorders Division and Director of the Columbia Translational Neuroscience Initiative
and of the Center for Motor Neuron Biology and Disease, Vagelos College of Physicians and Surgeons, Columbia University.

Description: 

Neurodegeneration represents a heterogeneous group of incurable disorders affecting the nervous system. It is characterized by the selective loss of specific subsets of neurons only. For decades, research in the field of neurodegeneration has primarily embraced a "neuronal-centric" view, focusing on the assumption that since clinical manifestations of these disorders, albeit varied, have been attributed to alterations in specific neural circuits, the disease process had to originate within neurons themselves.

However, there has been a growing interest and recognition in the involvement of non-neuronal cells in the pathogenesis of a host of neurodegenerative disorders. Thus, investigating the molecular mechanisms underlying neurodegeneration has led researchers, including ourselves, to explore the intriguing possibility of non-neuronal cell, particularly glial cells such as astrocytes – the most abundant cells in the central nervous system – involvement in disease pathogenesis.

We have endeavored to experimentally explore how disease-associated astrocytes may contribute to the neurodegenerative process. Utilizing mouse models of motor neuron degeneration caused by mutations in the enzyme superoxide dismutase 1 (SOD1), which are ubiquitously expressed in all cells, we have generated co-culture models comprising astrocytes expressing these genetic mutations and wild-type neurons. Our findings have revealed a neurodegenerative phenotype induced by these mutant astrocytes via a toxic gain-of-function mechanism.

To elucidate the nature of the mediating mutant astrocyte toxicity on neighboring wild-type neurons, we conducted both candidate-based and unbiased investigations. These led to the discovery of the potential role of a fragment of amyloid precursor protein (APP) generated by mutant astrocytes which, by binding to death receptor 6 on the neuronal side, transduces the death signal. The mechanisms underlying the production of this APP fragment by mutant astrocytes remain under investigation, but we hypothesize that aberrant handling of APP due to defects in retromer function in astrocytes expressing SOD1 mutations may be instrumental.

In conclusion, our work suggests that non-neuronal cells, particularly astrocytes, may play a significant role in neurodegeneration. Considering these cells in disease-modifying therapies and biomarker development may provide new avenues for combating these disorders effectively.

Room: 
F-1455
Location: 
Centre de recherche CERVO Brain Research Centre, 2601, de la Canardière Québec (Québec) CANADA G1J 2G3

Funding / Support / Partners

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