Mitochondrial and Endoplasmic Reticulum Alterations in a Case of Amyotrophic Lateral Sclerosis Caused by TDP-43 A382T Mutation

Abstract

Amyotrophic lateral sclerosis is the most common form of motor neuron disease. Mutations in TARDBP, the gene encoding the RNA-binding protein TDP-43, are responsible for about 5% of familial ALS. Here we report the clinical and biological features of an ALS patients with pA382T mutation in TPD-43 protein. Disease began with right hand muscles weakness, and equally involved upper and lower motor neuron with a classic phenotype, without cognitive impairment. While a family history of neurological diseases was reported, there was no evidence of familial frontotemporal dementia. Cultured fibroblasts from the patient were characterized by profound alterations of cell proteome, which impacts particularly the mitochondrial metabolic pathways and the endoplasmic reticulum. TDP-43 levels were similar to control, healthy fibroblasts, but a higher fraction localized in mitochondria. Mitochondrial network appeared fragmented, and the organelles smaller and more spheric. In agreement with impaired proteome and morphology of mitochondria, basal cell respiration was reduced. Mitochondrial DNA levels appeared normal. However, a higher amount of mitochondrial DNA was present in the cytosol, suggesting a pronounced mitochondrial DNA misplacement which can promote a pro-inflammatory response mediating by cGAS/STING. Thus, this case report further expands the clinical and pathological phenotype of A382T mutation.

TDP-43 dysregulation and neuromuscular junction disruption in amyotrophic lateral sclerosis

“…Mitochondrial dysfunction has been repeatedly described in cellular models expressing human wild-type TDP-43 or ALS variants (Q331K, M337V, A382T, I383T), including increased levels of mitochondrial ROS [ 124 ], activation of mitophagy [ 125 , 126 ], reduced basal respiration [ 127 ] and transmembrane potential [ 128 ], and deficiency in calcium uptake [ 129 ]. While TDP-43 is normally detected in mitochondria, this localization is increased in ALS patient specimens [ 130 ].…”

“…Abnormalities in mitochondrial morphology and distribution are a prominent TDP-43 phenotype [126,127,131,134,[136][137][138]. Furthermore, abnormal mitochondria have been shown to accumulate in presynaptic terminals of ALS patients [121], although this has been recapitulated inconsistently in TDP-43 transgenic mice.…”

A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations

“…Therefore, this raises the question as to whether the metabolic changes we observed were due to loss of the C-terminal part of the protein post residue 374? Interestingly, in a recent paper focused on TDP43 with an A382T mutation, isolated fibroblasts displayed fragmented mitochondria, reduced respiration and alterations in levels of TCA cycle and electron transport chain components (Zanini et al, 2022). These included DLD, pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1), the mitochondrial carrier SCL25A4, and many TCA cycle associated enzymes including isocitrate dehydrogenase 1 (IDH1), C1QBP, aconitase 2 (ACO2), citrate synthase (CS), dihydrolipoamide S-succinyltransferase (DLST), fumarate hydratase (FH) and malate dehydrogenase 2 (MDH2).…”

Unraveling Molecular and Genetic Insights into Neurodegenerative Diseases: Advances in Understanding Alzheimer’s, Parkinson’s, and Huntington’s Diseases and Amyotrophic Lateral Sclerosis

“…Further research is necessary to fully understand how this mutation leads to disease development and potential therapeutic approaches that target it. Genetic testing could prove invaluable in identifying individuals carrying this variant who may be at greater risk of ALS and related motor neuron diseases [ 157 , 158 ] ( Table 6 ).…”