Post by Chris Barry

The misguided view #parkinsonsdisease is a so-called 'synucleinopathy' has always been based on a foundation of quicksand. Following publication of Charles Piller's recent piece in SCIENCE on the disturbing allegations against Eliezer Masliah—who ranks first in the world in the total number of (co-)authored, peer-reviewed, synuclein-related papers in a #parkinsons context—we now know more about how that foundation was poured! I would hope Roche—which is codeveloping prasinezumab for PD with Prothena Corporation—is "...working to further understand the details of this matter" (as the Piller article indicates). Given Prothena's origin story and the fact numerous, now highly questionable Masliah papers are cited in Prothena patents, Prothena's statement "We do not interpret these claims as specifically relevant to the current prasinezumab clinical program" vis-à-vis the scientific misconduct allegations involving Eliezer Masliah strains credulity. Targeting α-synuclein in Parkinson's disease is destined to fail. Pathology does not drive disease, disease drives pathology. Counterintuitively, synaptic vesicle health and nerve terminal membrane lipid composition (MLC) in human CNS projection neurons are intimately and strikingly tied to the health of oligodendrocyte lineage cells. It is the obligatory “compensatory shift” from optimally constituted, high ethanolamine plasmalogen (PlsEtn) content synaptic vesicle (SV) membranes and high PlsEtn content nerve terminal plasma membrane (PM) inner leaflets to phosphatidylethanolamine (PE)-laden SV membranes and PE-laden nerve terminal PM inner leaflets occurring under the conditions of neuronal PlsEtn insufficiency which develop temporally downstream of Parkinson’s disease-triggering oligodendrocyte lineage cell injury that directly leads to the appearance of Lewy pathology—and, ultimately, to the demise of the various projection neurons known to be vulnerable in Parkinson’s disease...as explained in great detail in the underlying LinkedIn article. Lewy pathology is an epiphenomenon which occurs temporally downstream of perturbations of the fragile biophysics of neurotransmitter release from projection neurons. Sustaining those fragile biophysics requires healthy oligodendrocyte lineage cells! #drugdiscovery #drugdevelopment Brian Fiske Aligning Science Across Parkinson’s | ASAP Todd Sherer Shawn Ritchie Asa Abeliovich Tim Greenamyre