Genetics of Progressive Supranuclear Palsy

Abstract

Progressive supranuclear palsy (PSP) is a neurodegenerative syndrome that is clinically characterized by progressive postural instability, supranuclear gaze palsy, parkinsonism and cognitive decline. Pathologically, diagnosis of PSP is based on characteristic features, such as neurofibrillary tangles, neutrophil threads, tau-positive astrocytes and their processes in basal ganglia and brainstem, and the accumulation of 4 repeat tau protein. PSP is generally recognized as a sporadic disorder; however, understanding of genetic background of PSP has been expanding rapidly. Here we review relevant publications to outline the genetics of PSP. Although only small number of familial PSP cases have been reported, the recognition of familial PSP has been increasing. In some familial cases of clinically probable PSP, PSP pathologies were confirmed based on NINDS neuropathological diagnostic criteria. Several mutations in MAPT, the gene that causes a form of familial frontotemporal lobar degeneration with tauopathy, have been identified in both sporadic and familial PSP cases. The H1 haplotype of MAPT is a risk haplotype for PSP, and within H1, a sub-haplotype (H1c) is associated with PSP. A recent genome-wide association study on autopsyproven PSP revealed additional PSP risk alleles in STX6 and EIF2AK3. Several heredodegenerative parkinsonian disorders are referred to as PSP-look-alikes because their clinical phenotype, but not their pathology, mimics PSP. Due to the fast development of genomics and bioinformatics, more genetic factors related to PSP are expected to be discovered. Undoubtedly, these studies will provide a better understanding of the pathogenesis of PSP and clues for developing therapeutic strategies.

Keywords: Familial progressive supranuclear palsy; Genetics; MAPT; Microtubule-associated protein tau; Progressive supranuclear palsy.

Figure 1.

A schematic diagram showing exons of MAPT and locations of mutations. Mutations discovered in patients with progressive supranuclear palsy (PSP) or PSP-like phenotypes were marked in the upper half of the diagram and those with frontotemporal lobar degeneration presentation were marked in the lower half. E1 to E13 refer to number of exons. Note all mutations except for p.R5L are located in exon 10 or in stem-loop structure at the boundary between exon 10 and the intron following exon 10. Two mutations (p.L284R and p.S285R; marked with asterisk) were found only in patients with PSP phenotype.