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Progressive supranuclear palsy (PSP), a rare Parkinsonian disorder, is characterized by problems with movement, balance, and cognition. PSP differs from Alzheimer's disease (AD) and other diseases, displaying abnormal microtubule-associated protein tau by both neuronal and glial cell pathologies. Genetic contributors may mediate these differences; however, the genetics of PSP remain underexplored. Here we conduct the largest genome-wide association study (GWAS) of PSP which includes 2779 cases (2595 neuropathologically-confirmed) and 5584 controls and identify six independent PSP susceptibility loci with genome-wide significant (P < 5 × 10−8) associations, including five known (MAPT, MOBP, STX6, RUNX2, SLCO1A2) and one novel locus (C4A). Integration with cell type-specific epigenomic annotations reveal an oligodendrocytic signature that might distinguish PSP from AD and Parkinson's disease in subsequent studies. Candidate PSP risk gene prioritization using expression quantitative trait loci (eQTLs) identifies oligodendrocyte-specific effects on gene expression in half of the genome-wide significant loci, and an association with C4A expression in brain tissue, which may be driven by increased C4A copy number. Finally, histological studies demonstrate tau aggregates in oligodendrocytes that colocalize with C4 (complement) deposition. Integrating GWAS with functional studies, epigenomic and eQTL analyses, we identify potential causal roles for variation in MOBP, STX6, RUNX2, SLCO1A2, and C4A in PSP pathogenesis. The authors present the largest genome-wide association study to date for a rare Parkinsonian disorder, progressive supranuclear palsy (PSP). They include follow-up investigations of the identified susceptibility loci, functional consequences, and cell-specific pathologies, providing insights into genetic and molecular mechanisms underlying PSP. [ABSTRACT FROM AUTHOR]

Brain cell structure is a key determinant of neural function that is frequently altered in neurobiological disorders. Following the global loss of blood flow to the brain that initiates the postmortem interval (PMI), cells rapidly become depleted of energy and begin to decompose. To ensure that our methods for studying the brain using autopsy tissue are robust and reproducible, there is a critical need to delineate the expected changes in brain cell morphometry during the PMI. We searched multiple databases to identify studies measuring the effects of PMI on the morphometry (i.e. external dimensions) of brain cells. We screened 2119 abstracts, 361 full texts, and included 172 studies. Mechanistically, fluid shifts causing cell volume alterations and vacuolization are an early event in the PMI, while the loss of the ability to visualize cell membranes altogether is a later event. Decomposition rates are highly heterogenous and depend on the methods for visualization, the structural feature of interest, and modifying variables such as the storage temperature or the species. Geometrically, deformations of cell membranes are common early events that initiate within minutes. On the other hand, topological relationships between cellular features appear to remain intact for more extended periods. Taken together, there is an uncertain period of time, usually ranging from several hours to several days, over which cell membrane structure is progressively lost. This review may be helpful for investigators studying human postmortem brain tissue, wherein the PMI is an unavoidable aspect of the research.