The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity

Abstract

Genetic mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the increased presence of TDP-43 in the cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here, we have found that TDP-43 accumulates in mitochondria in neurons of subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. Within mitochondria, wild type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunit ND3 and ND6, impair their expression and specifically cause complex I disassembly. Suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose targeting TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration.

Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization

“…TDP-43 in mitochondria impairs mitochondrial bioenergetics, and the inhibition of TDP-43 mitochondrial localization suppresses its toxicity on mitochondrial function. 21 Not surprisingly, the significant reduction of the mitochondrial membrane potential (mDc) or oxygen consumption rate (OCR) noted in synaptic mitochondria isolated from brains of hemizygous TDP-43 M337V mice was also greatly alleviated by PM1 ( Figure 3C). PM1 alone did not change the basal levels of the mDc or OCR, which was consistent with our previous findings.…”

“…We previously characterized the specific amino acid motif that confers TDP43 mitochondrial localization. 21 The suppression of TDP-43 mitochondrial localization by either the deletion of motif M1 (AQFPGACGL), essential for its mitochondrial localization, or treatment with the M1 motif-based inhibitory peptide PM1 could block WT or mutant TDP-43-induced mitochondrial dysfunction and neuronal death in vitro and in mice. 21 Here, 11-to 12-monthold WT and transgenic mice were continuously infused with PM1 or control peptide (cPM) for 6 weeks (1.5 mg/kg/day, subcutaneously implanted ALZET pumps).…”

“…21 The suppression of TDP-43 mitochondrial localization by either the deletion of motif M1 (AQFPGACGL), essential for its mitochondrial localization, or treatment with the M1 motif-based inhibitory peptide PM1 could block WT or mutant TDP-43-induced mitochondrial dysfunction and neuronal death in vitro and in mice. 21 Here, 11-to 12-monthold WT and transgenic mice were continuously infused with PM1 or control peptide (cPM) for 6 weeks (1.5 mg/kg/day, subcutaneously implanted ALZET pumps). Consistent with our previous study, 21 murine TDP-43 (mTDP-43, recognized by a pan-TDP-43 antibody in WT mice) and human mutant TDP-43 (hTDP-43, recognized by an antibody specific to human TDP-43 in TDP-43 M337V mice) were present in highly purified mitochondria isolated from mouse brain tissues ( Figure 3A).…”

“…21 Here, 11-to 12-monthold WT and transgenic mice were continuously infused with PM1 or control peptide (cPM) for 6 weeks (1.5 mg/kg/day, subcutaneously implanted ALZET pumps). Consistent with our previous study, 21 murine TDP-43 (mTDP-43, recognized by a pan-TDP-43 antibody in WT mice) and human mutant TDP-43 (hTDP-43, recognized by an antibody specific to human TDP-43 in TDP-43 M337V mice) were present in highly purified mitochondria isolated from mouse brain tissues ( Figure 3A). We confirmed that PM1 reached the central nervous system and substantially reduced the levels of endogenous mTDP-43 in mitochondria in the brains of WT mice (data not shown).…”

“…In this study, we performed a battery of motor-coordinative and cognitive tests in adult hemizygous TDP-43 M337V Tg mice. Based on our most recent study identifying mitochondria as critical direct mediators for TDP-43-induced neurotoxicity, 21 we further tested whether the inhibition of mutant TDP-43 mitochondrial localization could reverse motor-coordinative and cognitive deficits in aged hemizygous TDP-43 M337V Tg mice after disease onset. We first monitored hemizygous TDP-43 M337V mice by body weight and commonly used behavioral tests relevant to motor and coordination function: rotarod and beam walk tests.…”