In mouse alpha-synuclein pathology, the seed-independent term followed Snca expression at rho 0.72, but 14 of 4,213 genes followed it more closely

An earlier study (sci:sha256:e4f996cb5252c2ac6c4115a94528c7ba7efec9fd44e13ce5aaf23789feeb2440) showed that the regional pattern of alpha-synuclein pathology in mice is dominated by a term that does not depend on the injection site, and that this term outranks connectome diffusion models when one site is fitted. Here we ask what that term is made of. We scored each of 213 Allen regions by its mean rank of pathology over 18 injection-site-by-time blocks of published mouse data (caudoputamen, nucleus accumbens and CA1 seeds, 1 to 24 months), leaving out blocks in which the region was itself injected. Across the 139 regions affected at least once, the score followed Snca expression at Spearman rho 0.72, region volume at 0.60 and connectome in-strength at 0.52, while out-strength and distance to the injection sites were null. Every p value came from Moran spectral randomization, which builds surrogate maps with the same spatial autocorrelation; the surrogates reproduced the observed Moran's I and gave null ranges as wide as plus or minus 0.57. Volume and in-strength were correlated at 0.77 and contributed little that was unique (partial rho 0.13 and 0.28), while Snca kept a partial rho of 0.67. With cross-validation on spatially contiguous held-out blocks, volume, in-strength and distance reached R2 0.19; adding Snca raised it to 0.59. However, Snca was not identified against the genome: 716 of 4,213 genes survived Benjamini-Hochberg control against the same spatial null, 14 genes correlated more strongly, and removing the first principal component of expression, which alone correlated at -0.66 with the score, cut Snca from rho 0.72 to 0.38 and from rank 16 to rank 65. An independent one-injection-site tau dataset followed none of these predictors, as expected when the seed-independent term cannot be separated from routing. Group means, an ordinal scale with a large floor, three forebrain seeds and region-averaged expression limit the test.

alpha-synuclein · selective vulnerability · Snca · gene expression · mouse connectome · spatial autocorrelation · Moran spectral randomization · pathology spread · spatial null models · structure and function