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GLUTAMATE-SPILLOVER DRIVES DISEASE PROGRESSION IN SPINOCEREBELLAR ATAXIAS
David Vc Britoand 6 co-authors
ABC-RI, Algarve Biomedical Center Research Institute, Universidade do Algarve
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS04-08PM-263
Presentation
Date TBA
Board: PS04-08PM-263
Event Information
Poster Board
PS04-08PM-263
Poster
View posterAbstract
Polyglutamine spinocerebellar ataxias (SCAs) comprise six rare inherited neurodegenerative disorders characterized by progressive ataxia, cerebellar atrophy and toxic protein aggregation. No disease-modifying therapy exists, and patients typically die 10–15 years after onset, underscoring the need for unconventional, mechanism-based interventions. Although neuronal hyperexcitability is increasingly implicated in SCA pathogenesis, the molecular drivers of excitotoxic degeneration in the cerebellum remain poorly defined. In other brain regions, activation of extrasynaptic N-methyl-D-aspartate receptors (NMDARs) is a key trigger of neurodegeneration; whether this pathway contributes to SCA2 and SCA3 is unknown.
We identified reduced levels of excitatory amino acid transporters (EAATs) in postmortem cerebellar tissue from SCA2 and SCA3 patients and in SCA mouse models, suggesting impaired glutamate clearance. Consistently, electrophysiological recordings in cerebellar slices revealed reduced synaptic NMDAR currents together with increased glutamate spillover, supporting aberrant activation of extrasynaptic NMDAR signaling. Because global NMDAR antagonism disrupts essential pro-survival functions and has largely failed clinically, we targeted a specific pathological node: the NMDAR–TRPM4 death-signaling complex.
We disrupted NMDAR/TRPM4 coupling using recombinant interface inhibitors (lentiviral delivery and transgenic expression) and a complementary small-molecule interference strategy. Both approaches reduced neuronal damage, insoluble aggregate deposition and neuroinflammation in cerebellar and extracerebellar regions, improved electrophysiological readouts, and robustly enhanced motor coordination across a four-month battery of five cerebellar-sensitive behavioral tasks.
Together, these findings implicate glutamate spillover–driven degeneration in SCA2 and SCA3 and establish NMDAR/TRPM4 interface inhibition as a promising disease-modifying therapeutic strategy for polyglutamine SCAs.
We identified reduced levels of excitatory amino acid transporters (EAATs) in postmortem cerebellar tissue from SCA2 and SCA3 patients and in SCA mouse models, suggesting impaired glutamate clearance. Consistently, electrophysiological recordings in cerebellar slices revealed reduced synaptic NMDAR currents together with increased glutamate spillover, supporting aberrant activation of extrasynaptic NMDAR signaling. Because global NMDAR antagonism disrupts essential pro-survival functions and has largely failed clinically, we targeted a specific pathological node: the NMDAR–TRPM4 death-signaling complex.
We disrupted NMDAR/TRPM4 coupling using recombinant interface inhibitors (lentiviral delivery and transgenic expression) and a complementary small-molecule interference strategy. Both approaches reduced neuronal damage, insoluble aggregate deposition and neuroinflammation in cerebellar and extracerebellar regions, improved electrophysiological readouts, and robustly enhanced motor coordination across a four-month battery of five cerebellar-sensitive behavioral tasks.
Together, these findings implicate glutamate spillover–driven degeneration in SCA2 and SCA3 and establish NMDAR/TRPM4 interface inhibition as a promising disease-modifying therapeutic strategy for polyglutamine SCAs.
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