PARKINSON'S DISEASE

Parkinson's disease is the most common neurodegenerative disease after Alzheimer's and the first cause of parkinsonian syndrome.
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DISEASE DESCRIPTION

SYMPTOMS

Characteristic symptoms of the disease are mainly motor disorders leading to akinesia (slowness of movement), muscle rigidity or hypertonia, slow and weak tremors, predominant sign of the pathology.

This disease leads to disability and a real loss of autonomy in the person suffering from this disease. Several treatments are currently available and allow quality of life improvement and decreased symptoms. However, these drugs are only successful on some patients and, basically, do not ensure curing this disease. This situation is due in part to brain damage late diagnosis at a time when they have become difficult to cure.

In fact, by the time the first symptoms of the disease occur, almost 80 % of neurons of substantia nigra (black substance), the small area of the brain destroyed by the disease, are already lost. The disease progresses in time and space : some other neurons will die in addition to dopaminergic neurons, and the histo-pathological stigma are first located in the lower parts of the brain to finally reach the cerebral cortex at an advanced stage of the disease.

In addition to deep brain stimulation, the current treatment consists in restoring normal dopamine concentrations or using dopamine mimetics, called agonists. As for Alzheimer’s disease and most major diseases of the nervous system, major challenges remain to reach new therapies. The first point is to understand the mechanisms of the disease at the cellular level to be able to block them. Then, it is necessary to be able to diagnose the disease early enough so that treatments can be effective ; it is finally necessary to identify the different forms of the disease, each of which may require special treatment.

CAUSES

Parkinson’s disease is a chronic neurodegenerative condition with slow development, characterised by the death of a population of neurons found in substancia nigra. These neurons, called dopaminergic, produce a molecule responsible for information transmission between neurons, dopamine, a neurotransmitter essential to body movement control. Progressive loss of these neurons and therefore decrease in dopamine concentration are the original cause of the disease. Motor symptoms appear when approximately 60-80% of these neurons are destroyed.

PREVALENCE

Parkinson’s disease is the second cause of motor disability in France. It affects 150 000 people in France, including 8000 new cases each year. Rare before 50, its occurrence increases after 60. Its incidence is slightly higher in men than in women whatever the age.

ICM RESPONSES

TOPICS AND RESEARCH TEAMS

HIGHLIGHTS

New gene involved in an early and very severe form of Parkinson’s disease

Suzanne Lesage and Olga Corti in Alexis Brice’s team have identified a new gene, VPS13C, involved in an early form of Parkinson’s disease. The protein it encodes is essential to neuron protection through maintenance of mitochondrial function. These results provide a better understanding of the mechanisms leading to neuron degeneration, thus opening the way to new therapeutic approaches. Moreover, they will enable the establishment of a diagnostic tool for these very severe forms of the disease, in order to manage them as quickly as possible.

A mechanism protecting neurons from stress

Researchers from Alexis Brice’s team have discovered a mechanism protecting neurons from cell death. Olga Corti and her staff have just described a natural mechanism of mitochondria protection in an experimental model of Parkinson’s disease. This mechanism implies maintaining the expression of a mitochondrial protective enzyme, HSD17B10, under the effect of Parkin, which role in the degradation of damaged mitochondria is also well described. The loss of this new protective mechanism would contribute to mitochondria dysfunction and dopaminergic neuron degeneration in Parkinson’s disease, caused by the Parkin gene mutation.

Sleep-wake rhythm regulator, dopaminergic neuron survival factor

A significant proportion of hypothalamic neurons producing orexin, neuropeptide involved in the regulation of sleep-wake rhythms, disappears in Parkinson’s disease. Researchers from Etienne Hirsch’s team have demonstrated a direct interaction of these neurons with substantia nigra dopaminergic neurons, these ones which loss causes motor disturbances specific to the disease. These researchers also discovered that orexin acted as a survival factor for dopaminergic neurons by a mechanism involving a specific receptor. These observations suggest that a therapeutic approach to restore orexin neurotransmission in pd patients could halt the progression of the disease.

Treat walking disorders through deep brain stimulation

Walking and balance disorders, and falls associated with them, caused by Parkinson’s disease, constitute a major public health problem. ICM researchers have recently highlighted that a region of the brainstem is involved in walking control in Human and that its stimulation would reduce the troubles which can occur. Deep brain stimulation in this area improves walking and balance disorders in some patients with Parkinson’s disease. These preliminary results strengthen the knowledge on this area of the human brainstem, and pave the way for the development of new treatments.

CLINICAL RESEARCH

Identify markers to follow and predict the progression of the disease

The ICEBERG study conducted by Mary Vidailhet and Stéphane Lehéricy at the ICM on 330 patients, at risk individuals and healthy subjects over 7 years, aims to identify and validate markers to predict and follow the progression of lesions caused by Parkinson’s disease, from the onset of the first symptoms to the clinical expression stage. The current stage focuses on biomarker research. A marker has been identified in a pre-symptomatic form of Parkinson’s disease, in which patients show isolated behaviour disorders in REM sleep. Researchers have indeed highlighted, by brain imaging, a signal decrease in a small structure of the brain stem. The major challenge for the coming years is to be able to :

slow down the evolution of Parkinson’s disease, limit disorders and develop personalised medicine
Prevent the onset of symptoms in at risk subjects through the development of both effective diagnostic tools and targeted therapeutics.

Understand the cause of compulsive disorders caused by drugs

The Badge-PD study conducted on 310 patients aims to search for potential genetic causes which may explain compulsive disorders observed in some patients in response to anti-parkinsonian treatments. The results of this multicentric and institutional study coordinated by professor Corvol are currently under analysis and will enable to improve patients care.

RESEARCH DEVELOPMENT

A therapeutic game for patient rehabilitation

The TOAP RUN game developed by BRAIN e-novation, joint lab between the ICM and the GENIOUS group, co-led by Marie-Laure Welter and Pierre Foulon was created to fight walking and balance disorders and falls in Parkinson’s disease. In this interactive game, the patient is a small animal, an athlete Toap, which has to collect coins placed in its path, while avoiding obstacles ! The first results of the ongoing clinical trial within the ICM are extremely encouraging, they showed very good acceptability and adherence to the game and a strong reduction of falls in patients, objective walking and instability improvement with reduced fear of falling. This project is the laureate of the World Innovation Competition– Phase1.

Fighting against involuntary movements

The ICM and CleveXel Pharma, pharmaceutical company led by Christian Bloy, have just started a phase II clinical trial within the CIC, to assess the effectiveness of a molecule, CVXL-0107, against motor fluctuations and involuntary movements (dyskinesias) induced by the standard treatment of Parkinson’s disease, L-Dopa.

A smartphone application for daily patient follow up

An application developed by AD SCIENTIAM, a start-up incubated at the ICM and directed by Liouma Tokitsu, enables to study the fluctuations of pd patients’ symptoms in everyday life. This application is distributed nationally in the entire NS-PARK network. This network brings together 24 clinical research centers supporting patients with Parkinson’s disease and movement disorders. It aims at promoting clinical trials to develop drugs improving patients’ lives.