TDP-1/TDP-43 potentiates human α-Synuclein (HASN) neurodegeneration in Caenorhabditis elegans

https://doi.org/10.1016/j.bbadis.2020.165876Get rights and content
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Highlights

  • Tdp-1 knock-out animals had decreased mRNA and protein levels of α-synuclein suggesting that TDP-1 supports its expression.

  • Tdp-1 knock-outs in α-synuclein overexpressing strains displayed decreased protein aggregates.

  • TDP-43 and α-synuclein co-overexpression showed increased neuronal pathology compared to transgenes expressed individually.

  • Overexpressing human TDP-43 and α-synuclein in C. elegans may serve as a novel invertebrate model of Lewy Body Dementia.

Abstract

TAR DNA binding protein (TDP-43) is a DNA/RNA binding protein whose pathological role in amyotrophic lateral sclerosis (ALS) and frontal temporal lobe dementia (FTLD) via formation of protein aggregates is well established. In contrast, knowledge concerning its interactions with other neuropathological aggregating proteins is poorly understood. Human α-synuclein (HASN) elicits dopaminergic neuron degeneration via protein aggregation in Parkinson's disease. HASN protein aggregates are also found in TDP-43 lesions and colocalize in Lewy Body Dementia (LBD). To better understand the interactions of TDP-43 and HASN, we investigated the effects of genetic deletion of tdp-1, the Caenorhabditis elegans ortholog of human TDP-43, as well as overexpression of TDP-43, in transgenic models overexpressing HASNWT and HASNA53T. Tdp-1 deletion improved the posture, movement, and developmental delay observed in transgenic animals pan-neuronally overexpressing HASNA53T, and attenuated the loss and impairment of dopaminergic neurons caused by HASNA53T or HASNWT overexpression. Tdp-1 deletion also led to a decrease in protein level, mRNA level and aggregate formation of HASN in living animals. RNA-seq studies suggested that tdp-1 supports expression of lysosomal genes and decreases expression of genes involved in heat shock. RNAi demonstrated that heat shock proteins can mediate HASN neuropathology. Co-overexpression of both human TDP-43 and HASNWT resulted in locomotion deficits, shorter lifespan, and more severe dopaminergic neuron impairments compared to single transgenes. Our results suggest TDP-1/TDP-43 potentiates HASN mediated neurodegeneration in C. elegans. This study indicates a multifunctional role for TDP-1/TDP-43 in neurodegeneration involving HASN.

Abbreviations

AD
Alzheimer's disease
ALS
amyotrophic lateral sclerosis
ADE
anterior deirid neurons
BP
biological process
CC
cellular component
C. elegans
Caenorhabditis elegans
CEP
cephalic neurons
DANs
dopaminergic neurons
FTLD
frontotemporal lobar degeneration
GO
Gene Ontology
HASN
human α-synuclein
HASNWT
human α-synuclein (wild type)
HASNA53T
human α-synuclein(A53T)
HASNWT OX
HASNWT pan-neuronally overexpressing
HASNA53T OX
HASNA53T pan-neuronally overexpressing
HSPs
heat shock proteins
IPTG
Isopropyl β-D-1-thiogalactopyranoside
KEGG
Kyoto Encyclopedia of Genes and Genomes
LBD
Lewy Body Dementia
MF
molecular function
NGM
Nematode Growth Media
NS
no significance
PD
Parkinson's disease
qRT-PCR
quantitative Real Time PCR
RNA-seq
RNA sequencing
RNAi
RNA interference
TDP-43
TAR DNA binding protein-43
TDP-43 OX
human TDP-43 pan-neuronally overexpressing
tdp-1 KO
tdp-1 knock-out (homozygote)
WT
wild type

Keywords

α-Synuclein
TDP-1/TDP-43
tdp-43
Parkinson's disease
Lewy body dementia
C. elegans
Neurodegeneration

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