What are the biological mechanisms of Charcot's disease?

The pathophysiological mechanisms behind the degeneration of motor neurons in ALS are still poorly understood. The discovery of genetic mutations associated with the disease has made it possible to identify a number of them.
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Discovered in 2011, the C9ORF72 gene mutation is present in around 40% of familial forms of ALS, 30% of familial forms of FTD, and 70% of patients suffering from both FTD and ALS. In 2006, toxic aggregations of the TDP-43 protein were also identified in these diseases. It is now known that they are present in 95% of cases of ALS, all forms combined (familial and sporadic), and 60% of FTD. The discovery of these aggregates common to both diseases has provided a molecular basis for the clinical continuum long observed by doctors. In addition, all carriers of the mutated C9ORF72 gene also show aggregates of TDP-43, although no physiological link between the two, or their interactions, has yet been clearly identified.


Disruption of autophagy?

One of the suspected reasons for the presence of these toxic aggregates is a defect in the recycling of waste products within the cells. The Ubiquilin 2 gene (UBQLN2) is one of the genes implicated in the development of ALS. This gene is necessary for the degradation of waste products in neurons. A study conducted by several teams at the Institut du Cerveau in collaboration with the University of Limoges looked at mutations in UBQLN2. Using functional studies, the researchers demonstrated that one of the cell degradation pathways, autophagy, was impaired in patients with a mutation in Ubiquilin 2.


Chronic inflammation

It has long been known that protein aggregates in the brain, such as amyloid plaques in Alzheimer’s disease or a-synuclein in Parkinson’s disease, are sources of inflammation, but this remains to be elucidated in the case of TDP-43.

The role of microglia, the resident immune cells of the nervous system, in the disease is now well accepted. The spinal motor neurons affected in ALS are unique in that they are surrounded both by microglial cells in the spinal cord and by peripheral macrophages in the nerve, which contain the part of the motor neuron that exits the spinal column to connect the muscle to the periphery. Until recently, the role of macrophages was the subject of debate. In 2020, Séverine Boillée’s team at the Institut du Cerveau demonstrated for the first time an important role for peripheral macrophages in the progression of ALS. Like microglia, macrophages generate a chronic inflammatory state that is deleterious to motor neurons. The advantage of macrophages is that they are easier to target from the periphery than microglial cells in the central nervous system.

For more information: https://institutducerveau-icm.org/fr/actualite/sclerose-laterale-amyotrophique-sla-maladie-de-charcot/


At the Paris Brain Institute

Using patient cells to model cellular interactions in ALS

Delphine BOHL’s objective in Séverine BOILLEE’s team is to model the disease using human induced pluripotent stem cells (iPSCs). This cutting-edge technology makes it possible to generate all types of cells, including motor neurons and immune cells, from patient skin cells (biopsies). iPSCs have two major capabilities: they can multiply infinitely and differentiate into any cell type in the body, provided they are exposed to the right signals. These new cell models are an invaluable tool, providing access for the first time to human neurons from patients. The first step is to be able to characterise very precisely the motor neurons obtained from patients’ iPSC cells, firstly in genetic cases, where the mutation causing ALS is known, and then in sporadic cases in order to identify possible common mechanisms. The second stage is to bring together motor neurons and immune cells in the same highly controlled environment in order to model their interactions. Ultimately, these models could also be used to test the efficacy of therapeutic molecules.