Burré Laboratory

Mutations in STXBP1 are associated with Ohtahara syndrome, West syndrome, and Dravet syndrome. These syndromes are devastating infantile epileptic encephalopathies, characterized by progressive cerebral dysfunction, leading to cognitive, sensory and/or motor function deterioration due to unremitting epileptic activity. STXBP1 is a neuronal protein which is essential for neurotransmitter release. Since 2008, more than 30 de novo mutations have been identified in the STXBP1 gene, which are linked to these seizure disorders. Yet, the impact of mutations on STXBP1 function is unknown. The goal of this grant is to investigate how disease-linked mutations in STXBP1 affect its function in vitro.

The interplay and contribution of α-, β- and γ-synuclein to the pathogenesis of diseases termed synucleinopathies is unknown. Synucleins are abundantly expressed in the brain, where they  localize to synaptic terminals. Yet, despite 25 years of research, their normal function remains unknown. Similarly, it remains enigmatic how synucleins trigger devastating diseases such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy, frontotemporal dementia, and Gaucher’s disease. The goal of this grant is to investigate the interplay of α-, β- and γ-synuclein with regard to their physiological functions and pathological activities.

Age is the biggest risk factor for developing Parkinson’s disease (PD), and α-synuclein pathology is a causal link to PD. In nerve terminals, α-synuclein cycles between a membrane-bound pool on synaptic vesicles and a cytosolic pool, and we have previously found that membrane-binding of α-synuclein protects it from aggregation. Yet, our understanding of age-dependent dynamics in intracellular α-synuclein pools is poor. The goal of this grant is to determine age-dependent changes in the subcellular localization of α-synuclein that lead to α-synuclein aggregation and pathology, and to identify triggers for this altered localization.
 

The goal of this grant is to reverse the specific dysfunctions caused by mutant STXBP1 using a small molecule approach.

The goal of this grant is to identify the disease mechanism underlying Munc18-1 linked infantile epilepsies, and to develop rescue strategies to combat pathogenic events.

The purpose of this grant is to generate mutants of alpha-synuclein that raise its membrane-bound state and to characterize these mutants regarding function and dysfunction.