Valproate Attenuates 25-kDa C-Terminal Fragment of TDP-43-Induced Neuronal Toxicity via Suppressing Endoplasmic Reticulum Stress and Activating Autophagy

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease. To date, there is no any effective pharmacological treatment for improving patients' symptoms and quality of life. Rapidly emerging evidence suggests that C-terminal fragments (CTFs) of TAR DNA-binding protein of 43 kDa (TDP-43), including TDP-35 and TDP-25, may play an important role in ALS pathogenesis. Valproate (VPA), a widely used antiepileptic drug, has neuroprotective effects on neurodegenerative disorders. As for ALS, preclinical studies also provide encouraging evidence for multiple beneficial effects in ALS mouse models. However, the potential molecular mechanisms have not been explored. Here, we show protective effects of VPA against TDP-43 CTFs-mediated neuronal toxicity and its underlying mechanisms in vitro. Remarkably, TDP-43 CTFs induced neuronal damage via endoplastic reticulum (ER) stress-mediated apoptosis. Furthermore, autophagic self-defense system was activated to reduce TDP-43 CTFs-induced neuronal death. Finally, VPA attenuated TDP-25-induced neuronal toxicity via suppressing ER stress-mediated apoptosis and enhancing autophagy. Taken together, these results demonstrate that VPA exerts neuroprotective effects against TDP-43 CTFs-induced neuronal damage. Thus, we provide new molecular evidence for VPA treatment in patients with ALS and other TDP-43 proteinopathies.

Ultrastructural studies of ALS mitochondria connect altered function and permeability with defects of mitophagy and mitochondriogenesis

“…TDP-43 metabolism is impaired by autophagy inhibitors which produce misplacement of TDP-43, while this is reversed under the effects of autophagy activation (Wang et al, 2010 ). In line with this, valproate attenuates neuronal toxicity by enhancing autophagy (Wang et al, 2015 ), while high levels of fragments from TDP-43 engulf the autophagy machinery causing motor deficits (Caccamo et al, 2015 ). Some fALS patients feature mutations of sequestosome 1 (SQSTM1; Fecto et al, 2011 ; Rubino et al, 2012 ).…”

The Pathobiology of TDP-43 C-Terminal Fragments in ALS and FTLD

“…Although it has been reported that the adaptor protein sequestresome 1 (p62/SQSTM1), which transports ubiquitinated proteins for proteasomal degradation, decreases aggregation of full-length TDP-43 as well as 15 and 25 kDa fragments (Brady et al, 2011), another study found p62 overexpression specifically lowered levels of CTF-35 but not full-length TDP-43 (Tanji et al, 2012). The proteasome has been shown to degrade a broad range of TDP-43 variants, including the full-length protein, disease-linked mutants and CTFs (Scotter et al, 2014; Chou et al, 2015; Wang X. et al, 2015; Crippa et al, 2016; Cicardi et al, 2018). However, CTF-25 is more sensitive to degradation by autophagy than CTF-35 or full-length TDP-43, as demonstrated by pharmacological inhibition or activation of the autophagy pathway (Scotter et al, 2014; Wang X. et al, 2015; Crippa et al, 2016; Cicardi et al, 2018).…”

“…The proteasome has been shown to degrade a broad range of TDP-43 variants, including the full-length protein, disease-linked mutants and CTFs (Scotter et al, 2014; Chou et al, 2015; Wang X. et al, 2015; Crippa et al, 2016; Cicardi et al, 2018). However, CTF-25 is more sensitive to degradation by autophagy than CTF-35 or full-length TDP-43, as demonstrated by pharmacological inhibition or activation of the autophagy pathway (Scotter et al, 2014; Wang X. et al, 2015; Crippa et al, 2016; Cicardi et al, 2018). VCP has been shown to be important for functional autophagy (Ju et al, 2009), and mutations to VCP cause rare cases of FTLD-TDP type D. This suggests a potential link between VCP and the clearance of TDP-43.…”

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

“…Small molecules that induce autophagy were shown to be neuroprotective in murine models of ALS (Sugai et al, 2004; Wang et al, 2012, 2015b). Over-expression of p62/SQSTM1 decreases TDP-43 accumulation and aggregation in cell culture, by stimulating protein degradation via autophagy and the proteasome (Brady et al, 2011).…”