biostudies-literatureTallon CNational Institute of Neurological Disorders and StrokeNational Multiple Sclerosis SocietyNCCIH NIH HHSNIA NIH HHSNational Cancer InstituteNINDS NIH HHSNational Institute of General Medical SciencesNIGMS NIH HHS274-288https://www.ebi.ac.uk/biostudies/studies/S-EPMC9130402biostudies-literatureUnknown19(1)Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease where muscle weakness and neuromuscular junction (NMJ) denervation precede motor neuron cell death. Although acetylcholine is the canonical neurotransmitter at the mammalian NMJ synapse, glutamate has recently been identified as a critical neurotransmitter for NMJ development and maintenance. One source of glutamate is through the catabolism of N-acetyl-aspartyl-glutamate (NAAG), which is found in mM concentrations in mammalian motoneurons, where it is released upon stimulation and hydrolyzed to glutamate by the glial enzyme glutamate carboxypeptidase II (GCPII). Using the SOD1^G93A model of ALS, we found an almost fourfold elevation of GCPII enzymatic activity in SOD1^G93A versus WT muscle and a robust increase in GCPII expression which was specifically associated with activated macrophages infiltrating the muscle. 2-(Phosphonomethyl)pentanedioic acid (2PMPA) is a potent GCPII inhibitor which robustly blocks glutamate release from NAAG but is highly polar with limited tissue penetration. To improve this, we covalently attached 2PMPA to a hydroxyl polyamidoamine (PAMAM-G4-OH) dendrimer delivery system (D-2PMPA) which is known to target activated macrophages in affected tissues. Systemic D-2PMPA therapy (20 mg/kg 2PMPA equivalent; IP 2 × /week) was found to localize in muscle macrophages in SOD1^G93A mice and completely normalize the enhanced GCPII activity. Although no changes in body weight or survival were observed, D-2PMPA significantly improved grip strength and inhibited the loss of NMJ innervation in the gastrocnemius muscles. Our finding that inhibiting elevated GCPII activity in SOD1^G93A muscle can prolong muscle function and delay NMJ denervation may have early therapeutic implications for ALS patients.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeuticsDendrimer-2PMPA Delays Muscle Function Loss and Denervation in a Murine Model of Amyotrophic Lateral Sclerosis.PMC9130402R01 NS113140R01NS093416R25GM109441R01 AG068130R01 NS093416R01CA16105R25 GM109441K01 AT010984Sharma RNg JDonoghue AKambhampati SPThomas AGJoe TRSharma AKannan RMKannan SSlusher BSZhang ZSchulte MZhu XLiaw KTallon CfalseDendrimer-2PMPA Delays Muscle Function Loss and Denervation in a Murine Model of Amyotrophic Lateral Sclerosis.Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease where muscle weakness and neuromuscular junction (NMJ) denervation precede motor neuron cell death. Although acetylcholine is the canonical neurotransmitter at the mammalian NMJ synapse, glutamate has recently been identified as a critical neurotransmitter for NMJ development and maintenance. One source of glutamate is through the catabolism of N-acetyl-aspartyl-glutamate (NAAG), which is found in mM concentrations in mammalian motoneurons, where it is released upon stimulation and hydrolyzed to glutamate by the glial enzyme glutamate carboxypeptidase II (GCPII). Using the SOD1^G93A model of ALS, we found an almost fourfold elevation of GCPII enzymatic activity in SOD1^G93A versus WT muscle and a robust increase in GCPII expression which was specifically associated with activated macrophages infiltrating the muscle. 2-(Phosphonomethyl)pentanedioic acid (2PMPA) is a potent GCPII inhibitor which robustly blocks glutamate release from NAAG but is highly polar with limited tissue penetration. To improve this, we covalently attached 2PMPA to a hydroxyl polyamidoamine (PAMAM-G4-OH) dendrimer delivery system (D-2PMPA) which is known to target activated macrophages in affected tissues. Systemic D-2PMPA therapy (20 mg/kg 2PMPA equivalent; IP 2 × /week) was found to localize in muscle macrophages in SOD1^G93A mice and completely normalize the enhanced GCPII activity. Although no changes in body weight or survival were observed, D-2PMPA significantly improved grip strength and inhibited the loss of NMJ innervation in the gastrocnemius muscles. Our finding that inhibiting elevated GCPII activity in SOD1^G93A muscle can prolong muscle function and delay NMJ denervation may have early therapeutic implications for ALS patients.2022-01-01T00:00:00Z2022 Jan2026-06-20T03:19:56.816Z2025-02-19T03:31:06.021ZS-EPMC91304023498465110.1007/s13311-021-01159-7