The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies

Abstract

TAR DNA-binding protein 43 (TDP-43) is a highly conserved nuclear RNA/DNA-binding protein involved in the regulation of RNA processing. The accumulation of TDP-43 aggregates in the central nervous system is a common feature of many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Accumulating evidence suggests that prion-like spreading of aberrant protein aggregates composed of tau, amyloid-β, and α-synuclein is involved in the progression of neurodegenerative diseases such as AD and PD. Similar to those of prion-like proteins, pathological aggregates of TDP-43 can be transferred from cell-to-cell in a seed-dependent and self-templating manner. Here, we review clinical and experimental studies supporting the prion-like spreading of misfolded TDP-43 and discuss the molecular mechanisms underlying the propagation of these pathological aggregated proteins. The idea that misfolded TDP-43 spreads in a prion-like manner between cells may guide novel therapeutic strategies for TDP-43-associated neurodegenerative diseases.

Neurodegenerative disorders: Spread of misfolded protein aggregates

Further research is needed to determine how an aggregate-forming protein common to several neurodegenerative disorders propagates throughout the brain. Many neurodegenerative conditions involve aggregates created by ‘prion-like’ proteins, misfolded proteins that can confer their abnormal structure on neighboring healthy proteins, resulting in aggregates which spread rather like an infection. Hyung-Jun Kim at the Korea Brain Research Institute in Daegu, South Korea, and co-workers reviewed current understanding of the transactive response DNA-binding protein 43 (TDP-43), an aggregate-forming protein implicated in disorders such as Alzheimer’s disease and frontotemporal dementia. Growing evidence suggests that TDP-43 may spread in a prion-like fashion. TDP-43 is implicated in the onset of Alzheimer’s, and the spread of misfolded TDP-43 aggregates is closely tied to disease severity. More research is needed into how TDP-43 propagates in different tissues and central nervous system cells.