Current directions in tau research: Highlights from Tau 2020

Abstract

Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and taurelated mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research.

Tau mRNA Metabolism in Neurodegenerative Diseases: A Tangle Journey

“…Tauopathies comprise a group of proteinopathies of the human nervous system characterized by the assembly into filaments of tau proteins, alone or in association with other proteins. Among tauopathies are pathologies such as Alzheimer’s disease (AD), Pick’s disease (PiD), chronic traumatic encephalopathies (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease (AGD), frontotemporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17) and several other, rarer diseases [ 17 , 18 ]. Moreover, tau aggregates display distinct morphological and biochemical features between tauopathies.…”

“…In the brains of AD patients, tau aggregates are named neurofibrillary tangles (NFTs). NFTs are composed of two distinguishable intracellular assemblies, the paired helical filaments (PHFs) and the straight filaments (SFs) [ 18 ]. Besides affecting microtubule dynamics, pathogenic forms of tau are reported to affect nuclear pore localization, function and nucleocytoplasmic trafficking [ 19 , 20 ], induce heterochromatin relaxation [ 21 ], promote DNA damage [ 22 , 23 ], alter RNA stability and RNA export [ 24 , 25 , 26 ], promote ribosome instability [ 27 ] and activate transposable elements [ 28 , 29 ].…”

“…Indeed, tau-mediated aggregates are heterogeneous and neurodegenerative diseases that can be divided into 3R, 4R or 3R + 4R tauopathies according to the biochemical composition of tau inclusions. Moreover, several mutations in and around exon 10 were found to affect its splicing and consequently linked to tau pathogenesis (detailed below) [ 17 , 18 ]. In this sense, AD and CTE are classified as 3R + 4R tauopathies; PiD and some types of FTDP-17 are 3R tauopathies; the 4R tauopathies include AGD, CBD and PSP [ 17 , 18 , 38 ].…”

“…Moreover, several mutations in and around exon 10 were found to affect its splicing and consequently linked to tau pathogenesis (detailed below) [ 17 , 18 ]. In this sense, AD and CTE are classified as 3R + 4R tauopathies; PiD and some types of FTDP-17 are 3R tauopathies; the 4R tauopathies include AGD, CBD and PSP [ 17 , 18 , 38 ]. Recently, Bachmann and colleagues (2021) showed that in human SH-SY5Y neuroblastoma cells, 2N tau isoforms diminished axonal enrichment while 4R isoforms increased microtubule count.…”

“…All Tau isoforms comprises four domains: N-terminal domain (aa 1–150), proline-rich domain (PRD), microtubule binding domain (MTBD) and C-terminal domain (aa 369–441) ( Figure 2 ) [ 18 ]. The tau N-terminal domain, also known as projection domain, plays a role in signaling and protein interactions, acting as function regulator and contributing to tau’s physiological paperclip conformation by interacting with the C-terminal domain.…”