S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD

Abstract

Rare genetic mutations result in aggregation and spreading of cognate proteins in neurodegenerative disorders; however, in the absence of mutation (i.e., in the vast majority of “sporadic” cases), mechanisms for protein misfolding/aggregation remain largely unknown. Here, we show environmentally induced nitrosative stress triggers protein aggregation and cell-to-cell spread. In patient brains with amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), aggregation of the RNA-binding protein TDP-43 constitutes a major component of aberrant cytoplasmic inclusions. We identify a pathological signaling cascade whereby reactive nitrogen species cause S-nitrosylation of TDP-43 (forming SNO-TDP-43) to facilitate disulfide linkage and consequent TDP-43 aggregation. Similar pathological SNO-TDP-43 levels occur in postmortem human FTD/ALS brains and in cell-based models, including human-induced pluripotent stem cell (hiPSC)-derived neurons. Aggregated TDP-43 triggers additional nitrosative stress, representing positive feed forward leading to further SNO-TDP-43 formation and disulfide-linked oligomerization/aggregation. Critically, we show that these redox reactions facilitate cell spreading in vivo and interfere with the TDP-43 RNA-binding activity, affecting SNMT1 and phospho-(p)CREB levels, thus contributing to neuronal damage in ALS/FTD disorders.

The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis—Frontotemporal Dementia

“…Inclusions of TDP-43 and its mislocalization in the cytoplasm was also observed in VCP-mutated iPSCs-derived MNs (144,145) and in neuropathological examination of ALS patients (146,147). TDP-43 was found accumulated also in cytoplasm of circulating lymphomonocytes as well in lymphocytes and monocytes separately evaluated in ALS patients (148).…”

Neurons undergo pathogenic metabolic reprogramming in models of familial ALS

“…In addition to providing reducing power to antioxidant systems, G6PDH also has pro-oxidant activities – for example, both nitric oxide synthase (NOS) and NADPH oxidase use NADPH to generate oxidants (nitric oxide and ROS, respectively) [ [95] , [96] , [97] ]. A variety of studies suggest that reducing the function of NADPH oxidase [ [98] , [99] , [100] ] or NOS [ 16 , 101 , 102 ] confers benefits in ALS models. In addition, the dysregulation of G6PDH has been show to drive reductive stress, protein aggregation and cardiomyopathy in ∝B-Crystallin mutant mice [ 103 ].…”

“…Alterations in mitochondrial structure and function are commonly observed in adult-onset neurodegenerative diseases [ [1] , [2] , [3] , [4] , [5] , [6] , [7] , [8] ]. In ALS, mitochondrial dysfunction impairs the efficiency of electron transport chain (ETC) activity and ATP production [ [9] , [10] , [11] , [12] , [13] ] and leads to the accumulation of reactive oxygen and nitrogen species [ [14] , [15] , [16] ], abnormal handling of intracellular calcium and cytochrome C release and apoptosis [ 17 ]. The extent to which these alterations in mitochondrial function impair cellular operations is unclear.…”

Interplay between mitochondria and reactive oxygen and nitrogen species in metabolic adaptation to hypoxia in facioscapulohumeral muscular dystrophy: potential therapeutic targets

“…Oxidative and nitrosative stresses are potent activators of endoplasmic reticulum (ER)-stress and the unfolded protein response (UPR), which are increasingly recognized as important modulators of muscle health and disease [75]. In vitro, FSHD patientderived myotubes are characterised by altered proteostasis, accompanied by aggregation of the transcriptional repressor TAR DNA-binding protein 43 (TDP-43) [76], a mechanism recently found to be mediated by TDP-43 S-nitrosylation [77]. Likewise, proteomics has identified a putative role of DUX4-induced ER-stress in FSHD pathogenesis, possibly through the well-characterised Heat Shock Protein Family A Member 5 (HSPA5)-Eukaryotic Translation Initiation Factor 2A (elF2a) axis [78].…”