Rewatch this 3P-Seminar…
Bryan Killinger, Postdoc at Rush Medical Center discussing “Truncation of alpha-synuclein in the human appendix of synucleinopathy patients” and Konstantin Senkevich, Postdoc at McGill University presenting on “Approaches to the treatment of GBA-associated Parkinson’s disease”
Bryan explained that synucleinopathies are diseases that involve the pathogenic aggregation of alpha-synuclein. Molecular factors responsible pathogenic alpha-synuclein aggregation remain unclear. Truncation of alpha-synuclein can enhance aggregation kinetics. The human vermiform appendix contains abundant truncated alpha-synuclein proteoforms that could influence pathological aggregation. I will discuss our use of the top-down mass spectrometry approach to identify and quantify alpha-synuclein proteoforms in the vermiform appendix and substantia nigra of patients diagnosed with common synucleinopathies (i.e. Parkinson’s disease, dementia with Lewy bodies). In total, we have cataloged 66 distinct alpha-synuclein proteoforms with 24 distinct cleavage sites. Our results suggest that altered proteolytic processing alpha-synuclein occurs in both brain and appendix of synucleinopathy patients.
Konstantin discussed how mutations in the GBA gene, which encodes enzyme glucocerebrosidase (GCase), are the most common genetic risk factors associated with Parkinson’s disease (PD) with a frequency of up to 5-20% among patients. Several biochemical features were revealed in patients with PD associated with mutations in the GBA gene. Identification of these features allowed us to put forward a hypothesis about a possible prophylactic and therapeutic effect of restoration of GCase activity, as well as a decrease in the concentration of substrates in PD patients. During this talk, we will discuss the pathogenesis and possible approaches to the treatment of GBA-associated PD.