Parkinson’s disease is characterized mainly by the death of a certain type of neuron, the dopamine-secreting neurons called “dopaminergics,” which are preferentially located in a very small region of the brain, the black substance or “locus niger.”
Biological mechanisms of Parkinson's disease
Neurons, the brain’s well-known cells, communicate with each other through synaptic transmission, the synapse being the space between 2 neurons. If information from one end of the same neuron to the other transits through an electrical current called the action potential (or nerve influx), synaptic transmission requires the intervention of proteins.
These molecules are secreted by neurons upstream of the synapse and attach to specific receptors carried by the next neuron, called neurotransmitters.
Dopamine neurons use only one neurotransmitter to communicate with each other, and with other types of neurons: dopamine.
The black substance in the brainstem is a very small, lens-sized region made up of about 400,000 dopaminergic neurons. This region and the neurons that make it up form a network with other cerebral areas such as the striatum, a region very involved in the control of movements but also in cognitive and behavioural functions.
In Parkinson's disease, for reasons that are still unclear, dopaminergic neurons die progressively, leading to a slow decrease in the dopamine level in the black matter but also in the regions connected to this area.
The first symptoms of parkinson's disease are estimated to occur when 50% of the dopaminergic neurons have been affected.
In the surviving neurons, clusters of a particular α-synuclein protein called Lewy bodies are observed. These aggregates, found both in the cell body (close to the nucleus) and in neuronal processes (dendrites and axons), are responsible for the death of neurons and hence the progressive disappearance of dopamine.
In addition to α-synuclein deposits in neurons, the protein is found in other cell types and in the space between 2 neurons (the synapse), which explains the spread of the disease and neuronal degeneration.
Thus, deposits of the protein are observed outside the black substance, particularly in the olfactory bulb, in the dorsal motor nucleus of the wave, in the Coeruleus-subcoeruleus complex, and in the spinal cord of parkinsonian patients.
The same is true of the peripheral nervous system, particularly the salivary glands and certain organs such as the heart and digestive tract.
The α-synuclein aggregates outside the black matter explain the heterogeneity of “non-motor” symptoms observed in patients. These symptoms are now difficult to treat, but the recent discovery of the key role of α-synuclein opens up new avenues for treatment.
At Paris Brain Institute
The teams of Olga CORTI and Professor Jean-Christophe CORVOL and Stéphane HUNOT and Etienne HIRSH are working to better understand the molecular and cellular mechanisms that cause PARKINSON disease.
Olga CORTI and her team are trying to identify the physiological consequences of the mutations identified in familial cases of parkinson's disease, mechanisms that are the same in all patients. This team is particularly interested in the dysfunction of mitochondria, organelles that provide energy to the cell and ensure its survival. Mitochondrial dysfunction appears to play an important role in neuronal degeneration. In May 2019, this team identified a combination of proteins involved in the pathological mechanism of Parkinson's disease, a molecular association that can serve as a biomarker or therapeutic target.
The team of Etienne HIRSH and Stéphane HUNOT is particularly interested in the neuroinflammation that accompanies the degeneration of dopaminergic neurons in Parkinson’s disease and in particular the role of glial cells, the brain’s resident immune cells, such as astrocytes.
