Risk genes in progressive supranuclear palsy (PSP) affect integrity and function of microtubules

Progressive supranuclear palsy (PSP) is a tauopathy and has a multifactorial etiology. The genetic component comprises at least 15 genes with unrelated functions that increase risk for PSP with a high degree of certainty. The function of these genes in increasing risk for PSP is presently unknown. This study was undertaken to identify new pathological pathways of these genes/proteins in increasing risk for PSP. Identification of possible targets and pathways of these genes was investigated using publicly available databases. 13 out of 15 of the risk genes, i.e. MAPT, KANSL1, PLEKHM1, STX6, MOBP, EIF2AK3, DUSP10, APOE, RUNX2, TRIM11, NFASC, CNTN2, and LRRK2 target microtubules, and directly alter their function via variable mechanisms. We now present data that these pathways are predicted to involve common pathways strongly involving microtubule hemeostasis, such as vesicle transport of misfolded proteins to lysosomes and cellular export. Two genes (SLCO1A2 and C4A) are not obviously directly targeting microtubules. Mutations of the risk genes interfere with microtubular function and/or structure as they relate to axon formation/integrity, axon transport, intracellular organelle transport and communication, and cellular, microtubule - guided waste management. Microtubules may be thought of as a conveyor belt for the distribution of nutrients and waste management. Taken together these alterations include an increased risk of tau precipitation (MAPT) and are molecular drivers of neuronal degeneration in PSP. Although microtubular dysfunction has long been documented in PSP mainly based on the findings related to MAPT, this is the first study of the effect of risk genes in PSP. We demonstrate that most of these genes (13/15) also affect microtubular structure and function. These genes/proteins may also be biased towards neurodegeneration in motor neurons.