The pathophysiologic mechanisms of ALS causing motor neuron degeneration are still poorly understood. A number of genetic mutations associated with the disease have been identified.
The biological mechanisms of Charcot's disease?
Discovered in 2011, the C9ORF72 gene mutation is present in approximately 40% of family forms of ALS, 30% of family forms of DFT, and 70% of patients with both DFT/SLA pathologies. In 2006, toxic aggregations of the TDP-43 protein had also been identified in these diseases. It is now known that they are present in 95% of ALS cases, all forms combined (family and sporadic), and 60% of FTD. The discovery of these aggregates common to both pathologies has provided a molecular basis for this clinical continuum that has long been observed by physicians. On the other hand, all carriers of the mutated C9ORF72 gene also have TDP-43 aggregates, with no clear physiological link between the two and their interactions at present.
According to Elisa TEYSSOU et al, Acta Neuropathologica 2013, 125: 512-522.
Images generated (or produced?) by Professor Danielle SEILHEAN, pathologist in the team of Séverine BOILLEE
A Disruption of Autophagy?
One of the suspected reasons for the presence of these toxic aggregates is a defect in the recycling of waste within cells. The Ubiquiline 2 gene (UBQLN2) is one of the genes involved in the development of ALS. This is necessary for the degradation of waste in neurons. A study conducted by several teams from the Brain Institute in collaboration with the University of Limoges looked at mutations in UBQLN2. Through functional studies, the researchers found that one of the cellular degradation pathways, autophagy, was impaired in patients with a Ubiquiline 2 mutation.
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 disease is now well recognized. Spinal motoneurons affected by ALS have the unique feature of being surrounded by both microglial cells in the spinal cord and peripheral macrophages in the nerve that contain the portion of the motoneuron that exits the spinal column to connect the muscle to the periphery. However, the role of macrophages has been debated until recently. In 2020, the team of Séverine Boillée at the Brain Institute has shown for the first time an important role of peripheral macrophages in the progression of ALS. Like microglia, they generate a chronic inflammatory state deleterious to motoneurons. The interest of macrophages is that they are easier to target from the periphery than microglial cells in the central nervous system.
At Paris Brain Institute
Modelling ALS Cellular Interactions through Patient Cells
The objective of Delphine BOHL in the team of Séverine BOILLEE is to model the disease using human induced pluripotent stem cells (iPSCs). This state-of-the-art technology makes it possible to generate any type of cell, including motor neurons or immune cells from skin cells (biopsy) of patients. iPSCs have two major abilities: they are able to multiply infinitely and differentiate into any cellular type of the organism if they are exposed to the right signals. These new cell models are a valuable tool that allows for the first time access to human neurons from patients. The first step is to be able to characterise very precisely the motoneurons obtained from the iPSC cells of patients, first in genetic cases, where the mutation causing ALS is known, and then in sporadic cases in order to possibly identify common mechanisms. The second step is to bring the motor neurons and immune cells together in a very controlled environment to model their interactions. In the long term, these models would also test the efficacy of therapeutic molecules.
Protocol for the procurement of induced pluripotent stem cells (iPS) and their derivatives
