Page 119 - Read Online

Paraskervas et al. Neuroimmunol Neuroinflammation 2018;5:17 Neuroimmunology
DOI: 10.20517/2347-8659.2018.18 and Neuroinflammation

Commentary Open Access

The emerging TDP-43 proteinopathy

George P. Paraskevas , Mara Bourbouli , Ioannis Zaganas , Elisabeth Kapaki 1
1,2
1
2
1 Cognitive and Movement Disorders Clinic and Neurochemistry Unit, 1st Department of Neurology, School of Medicine, National
and Kapodistrian University of Athens, Athens 11528, Greece.
2 Neurology Laboratory of the Department of Neurology, School of Medicine, University of Crete, Crete 71003, Greece.
Correspondence to: Dr. George P. Paraskevas, Cognitive and Movement Disorders Clinic and Neurochemistry Unit, 1st
Department of Neurology, School of Medicine, National and Kapodistrian University of Athens, 72 Vas. Sofias Ave, Athens
11528, Greece. E-mail: geoprskvs44@gmail.com

How to cite this article: Paraskervas GP, Bourbouli M, Zaganas I, Kapaki E. The emerging TDP-43 proteinopathy. Neuroimmunol
Neuroinflammation 2018;5:17. http://dx.doi.org/10.20517/2347-8659.2018.18

Received: 3 Apr 2018 Accepted: 10 Apr 2018 Published: 10 May 2018
Science Editor: Athanassios P. Kyritsis Copy Editor: Guang-Zhe Zhu Production Editor: Cai-Hong Wang

Currently, neurodegenerative diseases are viewed as proteinopathies. In this context, a specific protein or
peptide is involved in the pathogenesis of the disease by missfolding, polymerization, reduced degradation
and final accumulation in the form of insoluble inclusions leading to neurodegeneration by various
interacting mechanisms . In Alzheimer’s disease extracellular beta amyloid peptides and intracellular
[1,2]
hyperphoshorylated tau proteins accumulate in the brain. In parkinsonian syndromes alpha synuclein
(α-Syn) or 4R tau isoforms are found in various cytoplasmic inclusions.

In about 50% of patients with frontotemporal lobar degeneration (FTLD) and about 90% of patients with
[3]
amyotrophic lateral sclerosis (ALS) , the responsible protein is the transactive response DNA binding
[4]
protein-43 (TDP-43), forming ubiquitinated inclusions. The two clinical conditions may coexist in the same
patient or the same family with TDP-43 being the major culprit in the ALS-FTLD spectrum .
[5]

[6]
In an elegant study, Dong and Chen extensively reviewed the pathogenetic mechanisms of ubiquitinated
TDP-43 in ALS, including abnormal aggregation with pathologic accumulation (oligo- and finally poly-
merization), redistribution from the nucleus to the cytoplasm, reduced clearance by autophagy and/or
the ubiquitine-proteasome system, neurotoxicity and/or loss of function, complex interactions with other
proteins and RNA affecting their function and prion-like behavior and spreading. Such an understanding
of TDP-43 and its role in the mechanisms of the resulting proteinopathy, may prove to be important in two
aspects, diagnosis and treatment.

© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

www.nnjournal.net