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Review
. 2019 Oct 22:10:1125.
doi: 10.3389/fneur.2019.01125. eCollection 2019.

Frontrunner in Translation: Progressive Supranuclear Palsy

Ali Shoeibi  1 , Nahid Olfati  1 , Irene Litvan  2
Affiliations
Review

Frontrunner in Translation: Progressive Supranuclear Palsy

Ali Shoeibi et al. Front Neurol. .

Abstract

Progressive supranuclear palsy (PSP) is a four-repeat tau proteinopathy. Abnormal tau deposition is not unique for PSP and is the basic pathologic finding in some other neurodegenerative disorders such as Alzheimer's disease (AD), age-related tauopathy, frontotemporal degeneration, corticobasal degeneration, and chronic traumatic encephalopathy. While AD research has mostly been focused on amyloid beta pathology until recently, PSP as a prototype of a primary tauopathy with high clinical-pathologic correlation and a rapid course is a crucial candidate for tau therapeutic research. Several novel approaches to slow disease progression are being developed. It is expected that the benefits of translational research in this disease will extend beyond the PSP population. This article reviews advances in the diagnosis, epidemiology, pathology, hypothesized etiopathogenesis, and biomarkers and disease-modifying therapeutic approaches of PSP that is leading it to become a frontrunner in translation.

Keywords: biomarker; epidemiology; etiopathogenesis; progressive supranuclear palsy; tauopathy; translational research.

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Figures

Figure 1
Figure 1
Twenty-five years of progress in progressive supranuclear palsy research. AD, Alzheimer's disease; CBD, corticobasal degeneration; CDK5, cyclin-dependent kinase 5; CXCR4, chemokine receptor type 4; FTDP-17, frontotemporal dementia with parkinsonism linked to chromosome 17; GSK-3, glycogen synthase kinase 3; MAPT, microtubule associated protein tau gene; MT, microtubule; NFT, neurofibrillary tangle; p-tau, phosphorylated tau; PET, positron emission tomography; PiD, Pick's disease; PSP, progressive supranuclear palsy; 3R, tau protein with 3 repeat domains; 4R, tau protein with 4 repeat domains.
Figure 2
Figure 2
Tau isoforms and conformations. Six tau isoforms result from alternate splicing of exons 2, 3, and 10 (E2, E3, and E10). Tau mutations that present with PSP-like phenotypes (boxes) are mainly located at exon 10 or its splice site. There is only one mutation (R5L) located outside exon 10 that causes a PSP phenotype with brainstem 4R-tau aggregates but also 3R-tau-containing aggregates in cortical areas (93).
Figure 3
Figure 3
When tau binds to microtubules the N-terminal half of the protein projects away. The extreme N-terminal end of tau contains a phosphatase-activation domain (PAD) (green) that has a role in the regulation of cargo delivery. In the normal paperclip conformation PAD is not exposed, preventing it from triggering the phosphatase-kinase cascade (PKC) and detachment of cargo from microtubule. Activation of PAD and PKC normally occurs at the site of cargo delivery. Abnormal tau phosphorylation (by priming kinases) leads to persistent exposure and activation of PAD and triggering of the PKC which involves overactivation of GSK3β (yellow). Impairment of the fast axonal transport subsequently ensues. In the aggregated form, the microtubule binding domains constitute the core of the filament with the N- and C-terminal regions forming a fuzzy coat around it.
Figure 4
Figure 4
MRPI 2.0 index. This index is the product of the ratios of pons to midbrain area (Pa/Ma), width of middle to superior cerebellar peduncles (MCPd/SCPd), and average third ventricle diameter (measured at three points) to the maximal frontal horn diameter [(3rd Vd 1+2+3/3)/FHd]. MRIPI 2.0 = (Pa/Ma) × (MCPd/SCPd) × (average 3rd Vd/FHd).
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