The Cellular Prion Protein Increases the Uptake and Toxicity of TDP-43 Fibrils

Abstract

Cytoplasmic aggregation of the primarily nuclear TAR DNA-binding protein 43 (TDP-43) affects neurons in most amyotrophic lateral sclerosis (ALS) and approximately half of frontotemporal lobar degeneration (FTLD) cases. The cellular prion protein, PrPC, has been recognized as a common receptor and downstream effector of circulating neurotoxic species of several proteins involved in neurodegeneration. Here, capitalizing on our recently adapted TDP-43 real time quaking induced reaction, we set reproducible protocols to obtain standardized preparations of recombinant TDP-43 fibrils. We then exploited two different cellular systems (human SH-SY5Y and mouse N2a neuroblastoma cells) engineered to express low or high PrPC levels to investigate the link between PrPC expression on the cell surface and the internalization of TDP-43 fibrils. Fibril uptake was increased in cells overexpressing either human or mouse prion protein. Increased internalization was associated with detrimental consequences in all PrP-overexpressing cell lines but was milder in cells expressing the human form of the prion protein. As described for other amyloids, treatment with TDP-43 fibrils induced a reduction in the accumulation of the misfolded form of PrPC, PrPSc, in cells chronically infected with prions. Our results expand the list of misfolded proteins whose uptake and detrimental effects are mediated by PrPC, which encompass almost all pathological amyloids involved in neurodegeneration.

PrPC as a Transducer of Physiological and Pathological Signals

“…As for other amyloids, treatment with TDP-43 fibrils induced a reduction in the accumulation of the misfolded form of PrP C , PrP Sc , in cells chronically infected with prions. Our results expand the list of misfolded proteins whose uptake and detrimental effects are mediated by PrP C , which encompass almost all pathological amyloids involved in neurodegeneration ( Scialo et al, 2021 ).…”

“…In the case of AD, we have mentioned that AβOs, Aβ fibrils and plaques, and Tau tangles appear in the brain of patients with AD and that certain of these species are related to the neurotoxicity and neurodegeneration. In other proteinopathies, amyloids and deposits of other proteins, such as TAR DNA-binding protein 43 (TDP-43), α-synuclein (α-syn), and Tau, are found ( Legname and Scialo, 2020 ; Scialo et al, 2021 ). In the following sections, how some of these proteins are interconnected with PrP C , and therefore, the role of PrP in the diseases linked to them are discussed.…”

“…Frontotemporal lobar degeneration (FTLD), a neurodegenerative syndrome in frontal and anterior temporal lobes ( Rabinovici and Miller, 2010 ), and ALS, a motor neuron disorder characterized by degeneration in the upper and lower motor neurons ( Prasad et al, 2019 ), are two distinct diseases that shared a histopathological hallmark: inclusion bodies composed of cytoplasmic deposits of the nuclear TDP-43 protein ( Scialo et al, 2021 ). Under physiological conditions, TDP-43 is a transcriptional repressor that binds to chromosomally integrated TAR DNA.…”

“…It was observed in vitro that TDP-43 fibrils bind to recombinant PrP C . Also, in vitro , it was shown that full-length mouse (Mu)PrP C as well as human (Hu)PrP C act as a membrane receptor of TDP-43 in its fibrillar conformation, inducing the formation of intracytoplasmic aggregates and cell death ( Scialo et al, 2021 ). In addition, the overexpression of PrP C in human and mouse cell lines was directly correlated with the internalization of TDP-43 fibrils.…”

“…In addition, the overexpression of PrP C in human and mouse cell lines was directly correlated with the internalization of TDP-43 fibrils. Increased internalization was associated with detrimental consequences in all PrP-overexpressing cell lines ( Scialo et al, 2021 ).…”