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English: Hypothetical model of the pathomechanisms of progressive supranuclear palsy (PSP). The accumulation of pathogenic tau protein (orange box) plays a key role in the pathomechanisms of PSP. 1) Genetic factors (yellow box): Mutations in the MAPT gene, encoding tau protein, are causative in rare autosomal-dominant frontotemporal dementias, some of which present with the PSP phenotype. However, in sporadic PSP, the H1 haplotype of the MAPT gene is associated with sporadic PSP.[90] In view that approximately 78% of controls and approximately 94% of patients exhibit the H1 haplotype, this is likely increasing susceptibility.[90] In addition, variants in MOBP, STX6, EIF2AK3 (also known as PERK) [91] and TRIM11[92] are associated with abnormal tau accumulation and dysmyelination (blue box). 2) Environmental factors (green box): Annonaceae fruits contain a toxic compound, annonacin. Annonacin is a potent inhibitor of the mitochondrial respiratory chain at the complex I level. Mitochondrial dysfunction and oxidative injury are responsible for pathogenic tau accumulation. Metal/chemical exposure and drinking well water/pesticides might be involved in mitochondrial dysfunction and oxidative injury. Furthermore, annonacin induces abnormal tau pathology as well as neurodegeneration. Stress is associated with the development of neurofibrillary tangles via glucocorticoids. Hypertension is associated with an increased risk for PSP by inducing the aggravation of tau pathology and neuroinflammation. Inflammation may be associated with pathological tau accumulation and neurodegeneration. The use of statins and estrogen replacement therapy (ERT) may protect against PSP by reducing inflammation. In contrast, the use of beta blockers may increase the risk for PSP by exacerbating neuroinflammation (light green arrow). High educational attainment is also a protective factor in PSP, but the roles of education in the pathomechanisms remain unclear. Factors that increase the risk of PSP are indicated by green arrows, while those that decrease the risk are indicated by black arrows. The light green arrow represents the possible mechanism of increased risk for PSP with weak certainty.