Protein conformation disorders

Abnormal protein conformation, deposition and proteotoxicity are common traits of progressive degenerative disorders of the brain causing relatively frequent diseases but also rare inherited syndroms.

The motor symptoms of Parkinson’s disease (PD) result from the loss of dopaminergic neurons in specific regions of the brain, foremost in 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. Diagnosis of PD is based on progressive symptoms with confirmation of cell loss by neuroimaging. Current treatments alleviates the motor symptoms of the disease including, in more progressed PD, surgery and deep brain stimulation. Prolonged use of dopamine-replacement therapies may lead to a complication called dyskinesia, characterized by abnormal involuntary movements. A pathological hallmark of PD is the deposition of the protein alpha-synuclein in Lewy bodies and indeed, variations in the gene encoding for alpha-synuclein cause an inherited PD form. This establishes a causative role for alpha-synuclein and a link between idiopathic and genetic PD forms. Our research aims at elucidating the pathophysiology of levodopa-induced dyskinesia and at identifying innovative measures for early diagnosis.

The protein Tau is involved in the development of several brain disorders, most prominently Alzheimer’s disease, and less frequent progressive tauopathies, including frontotemporal dementia and parkinsonism linked to chromosome 17 caused by variations in the gene encoding for Tau. The disorders are associated with the brain deposition of tau in fibrillary tangles. When deposited Tau present several characteristics modifications such as hyperphosphorylation and a pathological conformation. How this occurs and causes neuronal dysfunction is poorly understood, but the presence and distribution of tangles correlate well with the cognitive loss observed in patients afflicted by the disorder. Our research aims at investigating how aging may contribute to the development of tauopathies. One study is dedicated to the cellular mechanisms causing the age-dependent spreading of pathological Tau ultimately affecting most of the brain. Another study is investigating the impact of cell stress, in the form of DNA damage, on the biology of Tau. Our interest is also engaged in similar studies but on proteins associated to rare disorders of the brain, for example amyotrophic lateral sclerosis or Huntington’s disease.