TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response

Abstract

Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. Electron microscopy (EM) analyses of patient samples revealed prominent mitochondrial impairment, including abnormal cristae and a loss of cristae; these ultrastructural changes were consistently observed in both cellular and animal models of TDP-43 proteinopathy. In these models, increased TDP-43 expression induced mitochondrial dysfunction, including decreased mitochondrial membrane potential and elevated production of reactive oxygen species (ROS). TDP-43 expression suppressed mitochondrial complex I activity and reduced mitochondrial ATP synthesis. Importantly, TDP-43 activated the mitochondrial unfolded protein response (UPR mt ) in both cellular and animal models. Down-regulating mitochondrial protease LonP1 increased mitochondrial TDP-43 levels and exacerbated TDP-43-induced mitochondrial damage as well as neurodegeneration. Together, our results demonstrate that TDP-43 induced mitochondrial impairment is a critical aspect in TDP-43 proteinopathy. Our work has not only uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced our understanding of the pathogenic mechanisms for TDP-43 proteinopathy. Our study suggests that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases.

Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons

“…It should also be noted that our current illumination paradigm encompasses not only the somas but also the motor axons. Therefore, "resident" cytoplasmic opTDP-43, such as that included in mRNP granules undergoing axonal transport 50 and in mitochondria at the axon terminals 51,52 , could also be photoconverted in situ, thereby contributing to the acute toxicity that involves neuromuscular synapse destabilization. Spatially-resolved light stimulation, a major advantage of optogenetics, could identify such potentially multiple pathogenic origins in the future.…”

Intercellular transmission of a bacterial cytotoxic prion-like protein in mammalian cells

“…In parallel, protein factors mounting the defence against stress and envelope damage co-aggregate with RepA-WH1(A31V) amyloids (Molina-García et al, 2017). Altogether, bacteria viability is severely compromised by RepA-WH1 amyloidosis, in a way resembling some of the central mitochondrial routes found in human amyloidoses (Haelterman et al, 2014; Norambuena et al, 2018; Mathys et al, 2019; Wang et al, 2019). However, E. coli is not suitable for addressing the issues of cell-to-cell transmissibility of protein aggregates and the subsequent intracellular amyloid cross-aggregation, since this Gram-negative bacterium does not uptake large protein particles due to the insurmountable obstacle of its three-layered cell envelope.…”

Optogenetic modulation of TDP-43 oligomerization fast-forwards ALS-related pathologies in the spinal motor neurons

“…It should also be noted that our current illumination paradigm encompasses not only the somas but also the motor axons. Therefore, “resident” cytoplasmic opTDP-43, such as that included in mRNP granules undergoing axonal transport 47 and in mitochondria at the axon terminals 48, 49 , could also be photoconverted in situ , thereby contributing to the acute toxicity that involves neuromuscular synapse destabilization. Spatially-resolved light stimulation, a major advantage of optogenetics, could identify such potentially multiple pathogenic origins in the future.…”