Fig. 2

Emerging mediators of cytoskeletal and mitochondrial dysfunction in ALS. In 97% of ALS and FTLD cases, TDP-43 is mislocalized to the cytoplasm, where it causes significant disruption to the homeostatic functions of neurons. a Exposure of neurons to toxic levels of excitatory neurotransmitters, as observed in ALS, triggers caspase-mediated cleavage of the inhibitory domain of PKN1. Constitutive activation of PKN1 is pathologic and causes aberrant phosphorylation of neurofilaments, which accumulate in TDP-43-positive aggregates. Mislocalized TDP-43 also represses the translation of neurofilament mRNAs. These aberrations disrupt the correct stoichiometry of neurofilaments and prevent the correct assembly of neurofilament structures. b Cytoplasmic TDP-43 activates GSK-3β, which blocks the interaction between VAPB and PTPIP51. The disruption of the ER-mitochondria calcium cycling reduces mitochondrial Ca²⁺ levels, which impairs ATP synthesis and increases cytosolic Ca²⁺ levels,  resulting in removal of the Miro-kinesin complexes from microtubules and inhibition of mitochondrial motility. c In the absence of nuclear TDP-43, truncated STMN2 mRNA is produced and undergoes nonsense-mediated decay. The loss of STMN2 contributes to impaired axonal outgrowth. d Cytoplasmic TDP-43 enters the mitochondria and represses translation of respiratory complex I mRNAs encoding ND3 and ND6, causing mitochondrial dysfunction, production of mtROS and leakage of mitochondrial DNA (mtDNA). The cytoplasmic mtDNA activates the cGAS/STING pathway and triggers NF-kB and IFN-I signaling. e TDP-43 also disrupts PARKIN levels, limiting the ubiquitination of surface proteins on damaged mitochondria. Furthermore, dysfunctional TBK1 is implicated in certain subtypes of ALS, while mitophagy adaptor proteins such as OPTN and p62 are sequestered in TDP-43 aggregates in individuals with ALS or FTLD-ALS. In all, these disruptions are likely to impair mitophagy and give rise to the accumulation of severely damaged, dysfunctional mitochondria, which disrupt motor neuron functions in patients with ALS. f Mislocalized TDP-43 impairs proteasomal function. As a result, full-length and cleaved PINK1 form insoluble cytoplasmic aggregates