. Genetic, transcriptomic, histological, and biochemical analysis of progressive supranuclear palsy implicates glial activation and novel risk genes. 2023 Nov 13 10.1101/2023.11.09.565552 (version 1) bioRxiv.

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  1. Good science is built on replication and validation. This new paper makes an importation contribution to both.

    It is unclear why the heritability of PSP is so low, in contrast to the closely related disorders of frontotemporal dementia. This is good news for families affected by PSP, but a challenge for research into the causes and modifiable mechanisms of PSP.

    The paucity of autosomal dominance in PSP does not, however, mean there are no genetic signals to elucidate its etiology. International collaboration has been key to the assembly of increasingly large cohorts of people with PSP with whom to conduct genome-wide association, revealing variants in MAPT, STX6, EIF2AK3, MOBP, RUNX2, SLCO1A, SLC2A13 (close to LRRK2), KANSL1 (adjacent to MAPT) in one or more smaller GWAS. These genetic variants imply potential therapeutic strategies via tau proteostasis, unfolded protein response, inflammation, and more.  

    Farrell et al. build impressively on this former work, in three ways:

    • First, through a larger cohort, of ~2,700 people with PSP and ~5,500 controls. GWAS and eQTL confirms five of the susceptibility loci—MAPT, MOBP, STX6, RUNX2, SLCO1A2—beyond doubt.
    • Second, by neuropathological evidence in  more than 93 percent of cases. This diagnostic accuracy is especially important for a rare and heterogeneous disorder with phenotypic mimicry like PSP.
    • Third, by molecular and histological validation studies in human brain tissue. For example, the relevance of inflammation is suggested by the microglial expression of RUNX2, and the new susceptibility locus C4A is underscored by elevated C4A expression in brain tissue, with co-localization of tau aggregates in oligodendrocytic C4.

    Given the complexity of the HLA region, the histological evidence supporting immune pathways and a unique oligodendrocyte signature in PSP is of immediate therapeutic interest.

    Looking ahead, there remains the need to analyze the genetic influences on phenotypic variance and survival. And functional genomics, in vivo models, replication and experimental medicine studies are to be expected. To this end, Farrell et al represent an important step forward.

    View all comments by James Rowe

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