Guanabenz, which enhances the unfolded protein response, ameliorates mutant SOD1-induced amyotrophic lateral sclerosis

Abstract

Approximately 20% of familial amyotrophic lateral sclerosis (FALS) cases are caused by mutant superoxide dismutase type 1 (mtSOD1). Although the mechanisms of mtSOD1-induced toxicity remain poorly understood, evidence suggests that accumulation of misfolded SOD1 is fundamental to its toxicity and the death of motor neurons. Misfolded mtSOD1 can accumulate inside the endoplasmic reticulum (ER), leading to ER stress, with activation of the unfolded protein response (UPR). We have previously carried out genetic studies focused on PERK (which is an eIF2α kinase that is rapidly activated in response to ER stress and leads to a repression in translation) and GADD34 (which participates in the dephosphorylation of eIF2α). We reported that mtSOD1 transgenic mice that are haploinsufficient for PERK have a significantly accelerated ALS disease, while mtSOD1 mice that are haploinsufficient for GADD34 have a remarkably ameliorated disease. Guanabenz, a centrally acting oral drug approved for the treatment of hypertension, enhances the PERK pathway by selectively inhibiting GADD34-mediated dephosphorylation of eIF2α. We have now treated G93A mtSOD1 transgenic mice with guanabenz and found a significant amelioration of disease with a delay in the onset and prolongation of the early phase of disease and survival. Guanabenz-treated G93A mice have less accumulation of mtSOD1 and an enhanced phosphorylation of eIF2α at endstage. This study further emphasizes the importance of the PERK pathway in the pathogenesis of FALS and as therapeutic targets in ALS, and identifies guanabenz as a candidate drug for the treatment of ALS patients.

Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations

“…First, our results, like those of others studies, clearly show the UBQLN2 mutants disrupt proteostasis, leading to accumulation of misfolded proteins (13,(28)(29)(30)(31). Second, accumulating evidence suggests disturbance in proteostasis, particularly induction of the UPR, as central in disease pathogenesis caused by ALS mutations in SOD1 and C9ORF72 (45)(46)(47)(48)(49). Furthermore, disruption of proteasome function in motor neurons in mice leads to ALS-like pathology (50).…”

Complementary Roles of GADD34- and CReP-Containing Eukaryotic Initiation Factor 2α Phosphatases during the Unfolded Protein Response

“…One potential factor distinguishing the vulnerable and resistant neurons is their secretory load, or the production and export of synaptic vesicles. Consistent with identification of GADD34 as a major regulator of the secretome, haploinsufficiency of GADD34 ameliorated motor neuron disease in mutant SOD1 (mSOD1) transgenic mice (46). Guanabenz also reduced motor neuron loss in this ALS mouse model (47) with hallmarks of a stalled UPR, namely, reduced expression of Bip and CHOP.…”

New Zebrafish Models of Neurodegeneration

“…Three agents (salubrinal, guanabenz and phenazine) were found to rescue paralysis, neurodegeneration and oxidative stress, albeit through different parts of the ER stress pathway (Figure 1 D) [26]. These results show that the ER unfolded protein response is an important target for therapeutic development, and this has recently been borne out by guanabenz treatment in G93A mtSOD1 transgenic mice, which results in a delay in onset, elongation of the early disease phase, and lengthened survival [27,28]. This zebrafish research has therefore contributed directly to the identification of guanabenz, an approved drug for hypertension, as a priority drug to pursue for the treatment of ALS.…”