Post by Chris Barry

Exhilarating, January 2024-published empirical evidence from Araks Martirosyan et al., indicating there likely exists a subset of oligodendrocytes (OLs) in the human substantia nigra (SN) capable of synthesizing dopamine and packaging it into vesicles, that subset of OLs being discernible in the postmortem SN of neurologically-normal-at-death individuals and largely absent in the postmortem SN of sporadic #parkinsons sufferers, has just been followed up with the equally exciting observation by Sarah Jäkel, PhD, et al., in an 8 Jan 2025 PLoS Biology paper that, based on technological advances and the abundance of OLs in the human midbrain, the long-standing assumption the axons of human SN dopaminergic neurons are poorly myelinated “...may need to be re-evaluated, especially in the context of PD pathogenesis." Jäkel et al., also note “A better understanding of the non-cell-autonomous determinants of neuronal vulnerability (in #parkinsonsdisease)..." is required, leading me to reiterate that the changes in the conformational dynamics of α-synuclein which precede its aggregation are driven by subtle alterations in the membrane lipid composition (MLC) of CNS projection neurons (PNs) and, counterintuitively, those subtle MLC changes in PNs are driven by temporally upstream, PD-triggering OL lineage cell injury...speaking directly to the “better understanding of the non-cell-autonomous determinants of neuronal vulnerability (in PD)” to which the authors refer! The August 2023 observation in NATURE by Genevieve Konopka et al., that, with respect to human, chimpanzee, and rhesus macaque brains there exists "...a human-specific increase of oligodendrocyte progenitor cells (OPCs) and a decrease of mature oligodendrocytes across cortical tissues..," with human-specific gene regulatory changes being accelerated in OPCs, beautifully frames recent work from Hauke Werner et al., demonstrating (in mice) "...quinoid dihydropteridine reductase (QDPR) emerges as a highly specific marker for MATURE oligodendrocytes and myelin." QDPR is overwhelming OL-expressed in the human CNS; data link in comments. Given QDPR’s role in endogenous dopamine biosynthesis (participating in recycling the key tyrosine hydroxylase cofactor BH4), the Konopka-identified relative dearth of mature OLs in the human cortex (at least)—combined with seminal work from Paul Tesar's group demonstrating OL susceptibility to common household chemicals in the environment (link in comments)—strikingly underscores how human OL injury is likely to serve as the trigger for PD pathogenesis. Please see the granular explanation of the genesis of Lewy pathology in the accompanying LinkedIn article to gain a better understanding of the physiological reality OLs are temporally and functionally upstream of dopaminergic projection neurons as #drug targets in Parkinson's disease! Patrik Brundin Simon Stott Brian Fiske Diane Stephenson Roche AbbVie BIAL Aligning Science Across Parkinson’s | ASAP