Preprint Review Version 2 Preserved in Portico This version is not peer-reviewed

SH-SY5Y-derived neurons: A Human Neuronal Model System for Investigating TAU Sorting and Neuronal Subtype-Specific TAU Vulnerability

Version 1 : Received: 15 June 2020 / Approved: 16 June 2020 / Online: 16 June 2020 (09:41:46 CEST)
Version 2 : Received: 22 December 2020 / Approved: 23 December 2020 / Online: 23 December 2020 (10:30:47 CET)

How to cite: Bell, M.; Zempel, H. SH-SY5Y-derived neurons: A Human Neuronal Model System for Investigating TAU Sorting and Neuronal Subtype-Specific TAU Vulnerability. Preprints 2020, 2020060203 (doi: 10.20944/preprints202006.0203.v2). Bell, M.; Zempel, H. SH-SY5Y-derived neurons: A Human Neuronal Model System for Investigating TAU Sorting and Neuronal Subtype-Specific TAU Vulnerability. Preprints 2020, 2020060203 (doi: 10.20944/preprints202006.0203.v2).

Abstract

The microtubule-associated protein TAU is sorted into the axon in healthy brain neurons. Somatodendritic missorting of TAU is a pathological hallmark of many neurodegenerative diseases called tauopathies, including Alzheimer’s Disease (AD). Cause, consequence, and (patho)physiological mechanisms of TAU sorting and missorting are understudied, in part also due to the lack of readily available human neuronal model systems. The human neuroblastoma cell line SH-SY5Y is widely used for studying TAU physiology and TAU-related pathology in AD and related tauopathies. SH-SY5Y cells can be differentiated into neuron-like cells (SH-SY5Y-derived neurons) using various substances. This review evaluates whether SH-SY5Y-derived neurons are a suitable model for i) investigating intracellular TAU sorting in general, and ii) with respect to neuron subtype-specific TAU vulnerability. I) SH-SY5Y-derived neurons show pronounced axodendritic polarity, high levels of axonally localized TAU protein, expression of all six major human brain isoforms, and TAU phosphorylation similar to the human brain. As proliferative cells, SH-SY5Y cells are readily accessible for genetic engineering, stable transgene integration and leading-edge genome editing are valuable and promising tools for TAU-related studies. II) Depending on the used differentiation procedure, SH-SY5Y-derived neurons resemble cells of distinct subcortical nuclei, i.e. the Locus coeruleus (LC), Nucleus basalis (NB) and Substantia nigra (SN), all of which early affected in many tauopathies. This allows to analyse neuron-specific TAU isoform expression and intracellular localization, also in the context of vulnerability to TAU pathology. Limitations are e.g. the lack of mimicking age-related tauopathy risk factors and the difficulty to define the exact neuronal subtype of SH-SY5Y-derived neurons. In brief, this review discusses the suitability of SH-SY5Y-derived neurons for investigating TAU (mis)sorting mechanisms and neuron-specific TAU vulnerability in disease paradigms.

Subject Areas

SH-SY5Y-derived neurons; TAU sorting; neuronal identity; tauopathy; Alzheimer’s disease

Comments (1)

Comment 1
Received: 23 December 2020
Commenter: Michael Bell
Commenter's Conflict of Interests: Author
Comment: Changes to Version 1:
- slight modification of the title
- revised version of the Abstract
- Table of contents added
- slight modifications of the Introduction
- chapter "Neuronal polarity and total TAU expression" was revised and is now divided into two chapters: "Neuronal maturity" and "TAU expression & subcellular localization"
- modifications of the chapter "TAU phosphorylation state"
- new Table added, comparing SH-SY5Y-derived neurons and other neuronal cell models (Table 1)
- modification and reassembly of Figure 2
- Figure 2B was skipped and its content is now shown in Table 2
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