Targeting the Sigma-1 Receptor via Pridopidine Ameliorates Central Features of ALS Pathology in a SOD1G93A Model

Ionescu, Ariel; Gradus, Tal; Altman, Topaz; Maimon, Roy; Avraham, Noi Saraf; Geva, Michal; Hayden, Michael R.; Perlson, Eran

doi:10.1038/s41419-019-1451-2

Cited by 68 publications

(84 citation statements)

References 59 publications

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“…Pridopidine shows in vivo high S1R occupancy vs. low D2/D3R occupancy at behaviorally effective doses in rat brains using [ 11 C]SA4503 and [ 11 C] Raclopride PET [8]. Neuroprotective properties of pridopidine via S1Ractivation have been demonstrated previously in numerous preclinical models of NDD including HD, PD, and ALS [1,[13][14][15][16][17]. These effects of pridopidine are S1R-mediated, because genetic knock-down or pharmacological inhibition of S1Rs abolishes the pridopidine effects [14][15][16].…”

Section: Discussionmentioning

confidence: 95%

“…Importantly, S1R activation, e.g., by pridopidine, enhances neuroprotective effects in preclinical models of neurodegeneration, including HD and ALS, acting to stimulate brain repair and plasticity. Pridopidine augments brain-derived neurotrophic growth factor (BDNF) secretion and rescues dendritic spine loss and restores the aberrant calcium signaling via the S1R shown in experimental HD, Parkinson disease (PD), and ALS [13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

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Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study

Grachev

Meyer

Becker

et al. 2020

Eur J Nucl Med Mol Imaging

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Purpose Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [18F] fluspidine and [18F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD. Methods Using [18F] fluspidine PET (300 MBq, 0–90 min), 11 male HVs (pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (pridopidine 90 mg) were investigated twice, without and 2 h after single dose of pridopidine. Using [18F] fallypride PET (200 MBq, 0–210 min), four male HVs were studied without and 2 h following pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot. Results S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%). Conclusions Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine’s mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study

Grachev

Meyer

Becker

et al. 2020

Eur J Nucl Med Mol Imaging

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“…Taking into consideration our previous findings that muscle-dependent secretion of toxic factors can trigger axon degeneration in MNs and accelerate SOD1 G93A MN loss (Maimon et al ., 2018), we investigated whether muscle toxicity could also hamper MN cell survival. Similarly as described before (Maimon et al ., 2018; Ionescu et al ., 2019), WT or SOD1 G93A P60 gastrocnemius muscles were dissected and cultured in the distal compartment of the microfluidic chamber for 7 days. Then, WT ChAT::tdTomato or SOD1 G93A/ChAT::tdTomato explants were plated in the proximal compartment and grown in the Micro Fluidic Chambers (MFC) until axons traversed into the distal compartment and formed contact with the muscles.…”

Section: Resultsmentioning

confidence: 99%

Sema3A Facilitates a Retrograde Death Signal via CRMP4-Dynein Complex Formation in ALS Motor Axons

Maimon

Ankol

Weissova

et al. 2019

Preprint

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29Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease 30 with selective dysfunction; it causes the death of motor neurons (MNs). In spite of 31 some progress, currently no effective treatment is available for ALS. Before such 32 treatment can be developed, a more thorough understanding of ALS pathogenesis is 33 required. Recently, we demonstrated that ALS-mutated muscles contribute to ALS 34 pathology via secretion of destabilizing factors such as Sema3A; these factors trigger 35 axon degeneration and Neuromuscular Junction (NMJ) disruption. Here, we focus on 36 the molecular mechanism by which muscle contribute to MNs loss in ALS. We 37 identified CRMP4 as part of a retrograde death signal generated in response to 38 muscle-secreted Sema3A, in ALS-diseased MNs. Exposing distal axons to Sema3A 39 induces CRMP4-dynein complex formation and MN loss in both mouse (SOD1 G93A ) 40 and human-derived (C9orf72) ALS models. Introducing peptides that interfere with 41 CRMP4-dynein interaction in MN axons profoundly reduces Sema3A-dependent MN 42 loss. Thus, we discovered a novel retrograde death signal mechanism underlying MN 43 loss in ALS. 44 45 46 Summary 47 Maimon et al. identify a novel retrograde death mechanism that contribute to MN loss 48 in ALS, in which CRMP4-Dynein complex is form and retrogradely move along the 49 axon.50 51 52 53 105 Strittmatter, 2007). The canonical signaling events of CRMPs during Semaphorin 106 signaling involve their phosphorylation via GTPase activity, which further leads to 107 microtubule destabilization and axon retraction (Sasaki et al., 2002; Yamashita and 108 5 Goshima , 2012; Balastik et al., 2015). In addition to their role in mediating Sema3A 109 intrinsic responses, CRMPs were also reported to bind dynein and kinesin, and 110 modulate their function (Arimura et al., 2009; Rahajeng et al., 2010). Several studies 111 further demonstrated the involvement of CRMPs in neurodegenerative diseases 112 (Charrier et al., 2003; Yamashita and Goshima, 2012; Nagai, Baba and Ohshima, 113 2017). Specifically, CRMP4 expression levels were previously found to be elevated in 114 the SOD1 G93A mouse spinal cord, and were suggested to hamper MN health (Duplan 115 et al., 2010; Valdez et al., 2012; Nagai et al., 2015). However, the mechanism underline 116 the involvement of CRMP4 mediating cell death and its role in other ALS model is still 117 elusive. Moreover, mutations in CRMP4 were associated with ALS patients (Blasco et 118 al., 2013). 119 120 Here, we identified a novel retrograde death signal, triggered by Sema3A, which 121 facilitates MN loss in both murine and human ALS models. This process is mediated 122 by the formation of CRMP4-Dynein complex along diseased axons. Interfering with the 123 binding of CRMP4 to Dynein by using short blocking peptides rescues Sema3A-124 dependent MN loss in these ALS models. 125 126 Results 127 128 SOD G93A MNs and muscle co-cultures enhance MN loss 129 MN cell death is a key process in ALS pathology. Taking into consideratio...

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Section: Introductionmentioning

confidence: 99%

“…To study the effect of TDP-43 mislocalization on the NMJ in a precise and controlled environment, we used a neuromuscular co-culture setup in microfluidic chambers (MFCs) that we recently developed [28][29][30][31][32] . This platform can model several pathological features of ALS, such as axon degeneration, NMJ dysfunction and MN death 29,[33][34][35] . The fluidic separation between the motor neuron cell-body and axon allows the formation of functional NMJs exclusively at the distal compartment 29,[31][32][33][34][35][36] .…”

Section: Introductionmentioning

confidence: 99%

Axonal TDP-43 Drives NMJ Disruption through Inhibition of Local Protein Synthesis

Altman

Ionescu

Ibraheem

et al. 2020

Preprint

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Mislocalization of the predominantly nuclear RNA/DNA binding protein, TDP-43, occurs in motor neurons of ~95% of ALS patients, but the contribution of axonal TDP-43 to this fatal neurodegenerative disease is unclear. Here, we find TDP-43 accumulation in the axons of intra-muscular nerves from ALS patients, and in motor neurons and neuromuscular junctions (NMJs) of a mouse model with TDP-43 mislocalization. This leads to the formation of G3BP1- and TDP-43- positive RNA-granules in motor neuron axons, and to inhibition of local protein synthesis in axons and NMJs. Specifically, the axonal and synaptic levels of nuclear-encoded mitochondria proteins are reduced. Clearance of axonal TDP-43 restored local translation of the nuclear-encoded mitochondrial proteins and rescued TDP-43-derived axonal and NMJ toxicity. These findings suggest that targeting TDP-43 axonal gain of function may mediate a therapeutic effect in ALS.

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Targeting the Sigma-1 Receptor via Pridopidine Ameliorates Central Features of ALS Pathology in a SOD1G93A Model

Cited by 68 publications

References 59 publications

Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study

Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study

Sema3A Facilitates a Retrograde Death Signal via CRMP4-Dynein Complex Formation in ALS Motor Axons

Axonal TDP-43 Drives NMJ Disruption through Inhibition of Local Protein Synthesis

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