Parkinson disease and protein conformation disorders
Parkinson’s disease (PD) is a progressive degenerative disorder of the brain. The motor symptoms of PD result from the loss of dopaminergic neurons in specific regions of the brain, such as the substantia nigra. Dopaminergic neurons have an inhibitory function in the motor circuits of the brain and thus their loss cause an excessive and uncontrolled movement. PD is the second most frequent neurodegenerative disorder with most cases occurring after the age of fifty.
Diagnosis of PD is based on progressive symptoms with confirmation by neuroimaging. Current treatments (levodopa, dopamine agonists) alleviates the motor symptoms of the disease. In more progressed PD, surgery and deep brain stimulation can reduce motor symptoms. Prolonged use of dopamine-replacement therapies may lead to a complication called dyskinesia. Levodopa-induced dyskinesia is characterized by abnormal involuntary movements (dystonia, chorea, athetosis).
A pathological characteristic of PD is the deposition of the protein alpha-synuclein in Lewy bodies whose number and distribution directly correlates with the clinical symptoms. In few PD forms, variations in the gene encoding for alpha-synuclein cause an inhereted form of PD. This establishes a role for alpha-synuclein in disease initiation and progression as well as a link between idiopathic and genetic forms of PD.
Our research focus on the development of new animal models of the disease with the aim to elucidate the pathophysiology of levodopa-induced dyskinesia. Our molecular studies address the mechanisms leading to abnormal protein conformation, aggregation and toxicity of alpha-synuclein as a strategy for new therapies able to prevente or slow-down the progression of the disease.
Abnormal protein conformation, deposition and proteotoxicity are common traits of degenerative disorders such as Parkinson’s, Alzheimer’s, Huntington’s disease or amyotrophic lateral sclerosis.