Neurons, well-known brain cells, communicate with each other by means of synaptic transmission, the synapse being the space between 2 neurons. While information from one end of a neuron to the other is transmitted via an electrical current called the action potential (or nerve impulse), synaptic transmission requires the intervention of proteins.
These molecules are secreted by the neurons upstream of the synapse and bind to specific receptors carried by the next neuron; they are called neurotransmitters.
Dopaminergic neurons use a single neurotransmitter to communicate with each other and with other neurons: dopamine.
The substantia nigra in the brain stem is a very small region, about the size of a lens, and is made up of around 400,000 dopaminergic neurons. This region and the neurons that make it up form a network with other areas of the brain, such as the striatum, which is heavily involved in controlling movement, as well as cognitive and behavioural functions.
In Parkinson’s disease, for reasons that are still poorly defined, the dopaminergic neurons gradually die off, leading to a slow decline in dopamine levels in the substantia nigra and in the regions connected to this area.
It is estimated that the 1st symptoms of Parkinson’s disease appear when 50% of the dopaminergic neurons have been affected.
In surviving neurons, we see clusters of a particular protein, α-synuclein, known as Lewy bodies. These aggregates, which are found both in the cell body (close to the nucleus) and in the extensions of the neurons (dendrites and axons), are responsible for the death of the neurons and therefore for the gradual disappearance of dopamine.
In addition to deposits of α-synuclein 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 damage and neuronal degeneration.
Deposits of the protein are found outside the substantia nigra, particularly in the olfactory bulb, in the dorsal motor nucleus of the vagus, in the coeruleus-subcoeruleus complex and in the spinal cord of Parkinson’s patients.
The same is true of the peripheral nervous system, in particular the salivary glands and certain organs such as the heart and digestive tract.
The aggregates of α-synuclein outside the substantia nigra explain the heterogeneity of the “non-motor” symptoms observed in patients. These symptoms are currently difficult to treat, but the recent discovery of the key role of α-synuclein opens the way to new therapeutic avenues.
At the Paris Brain Institute
The teams led by Olga CORTI, Professor Jean-Christophe CORVOL, Stéphane HUNOT and Etienne HIRSH are working to gain a better understanding of the molecular and cellular mechanisms underlying PARKINSON’S disease.
Olga CORTI and her team are seeking to identify the physiological consequences of mutations identified in familial cases of Parkinson’s disease, mechanisms that are the same in all patients. The team is particularly interested in the dysfunction of mitochondria, organelles whose role is to supply energy to the cell and ensure its survival. Mitochondrial dysfunction appears to play a major 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 could serve as a biomarker or therapeutic target.
The team led by Etienne HIRSH and Stéphane HUNOT is particularly interested in the neuroinflammation concomitant with 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.