LRRC57/RABIN is a presynaptic inhibitor of Rab GTPases in glutamatergic neurons

At the Crossroads of Synapses and Signaling: The Role of LRRK2 in Neuronal Communication

How LRRK2-dependent trafficking mechanisms regulate key components of synaptic transmission, including glutamatergic and GABAergic receptors, as well as astrocytic transporters are examined, highlighting how disruption of these processes affects neurotransmitter clearance, receptor activation, and ultimately E/I balance.

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GABAA Receptor Trafficking Disruption in Epilepsy: From Assembly to Synaptic Dysfunction.

Epilepsy is a complex neurological disorder characterized by recurrent seizures resulting from an imbalance between excitatory and inhibitory neurotransmission. γ-Aminobutyric acid type A receptors (GABAARs), the principal mediators of fast inhibitory synaptic transmission, are essential for maintaining neuronal stability. Their function depends on tightly regulated trafficking processes, including subunit assembly in the endoplasmic reticulum, transport through the Golgi apparatus, membrane insertion, synaptic targeting, stabilization, and recycling. Disruptions in these processes, caused by genetic mutations, aberrant posttranslational modifications, or seizure-induced neuronal activity, impair receptor surface expression and localization, reducing inhibitory signaling and promoting network hyperexcitability. Evidence from human and animal studies indicates that altered GABAAR trafficking contributes to epileptogenesis and pharmacoresistance, particularly during severe conditions such as status epilepticus. Understanding the molecular mechanisms regulating GABAAR trafficking provides insights into epilepsy pathophysiology and highlights potential therapeutic strategies aimed at restoring inhibitory balance. By linking these trafficking mechanisms to synaptic structure and ion channel function, this review situates GABAAR biogenesis within the broader framework of synaptic organization relevant to epilepsy and other neurological disorders.

Alternative splicing of synaptotagmin 7 regulates oligomerization and short-term synaptic plasticity.

Synaptic plasticity is crucial for learning and memory. The presynaptic calcium sensor synaptotagmin 7 (syt7) regulates aspects of short-term plasticity (STP), but the underlying mechanisms remain unclear. Here, we show that alternative splicing of the syt7 juxtamembrane linker acts as a molecular switch at both biochemical and functional levels. The α and β variants undergo liquid-liquid phase separation to form condensates, while the γ variant forms aggregates. Using iGluSnFR imaging, we found that, when expressed at equal levels, these three isoforms also diverge regarding their abilities to regulate two key aspects of STP: paired-pulse facilitation and synaptic depression. Stimulated emission depletion microscopy showed that all three isoforms form active zone-associated clusters that colocalize with syt1, while minimal photon flux superresolution microscopy resolved syt7 clusters within the active zone, well-positioned to directly control synaptic vesicle dynamics. Thus, alternative splicing might fine-tune STP by differentially impacting syt7 oligomerization.

Integration of Semaphorin/Plexin activation and amplification by a Neuropilin-like coreceptor ensures robust homeostatic plasticity.

Robust homeostatic plasticity is essential for survival, enabling neuronal circuits to withstand destabilizing forces and restore function during critical challenges such as predator evasion or toxin exposure. Semaphorin/Plexin signaling is central to presynaptic homeostatic potentiation at central synapses and at neuromuscular junctions across species. However, our understanding of this pathway has remained incomplete, as secreted Semaphorins bind weakly to their Plexin receptors and require additional coreceptors for efficient signaling. Here, we identify Neuropilin and Tolloid-like protein (Neto-α), an auxiliary subunit for ionotropic glutamate receptors (iGluRs), and the tyrosine kinase Abelson (Abl) as essential components of the Sema2b/PlexB signaling pathway that drives rapid homeostatic potentiation and stabilizes synaptic strength at the Drosophila neuromuscular junction. Neto-α functions as a Neuropilin-like coreceptor that cooperates with Sema2b to relieve PlexB autoinhibition and initiate signaling. In parallel, Neto-α recruits Abl, which functions as a cytosolic amplifier to enhance pathway output. We demonstrate that both pathway activation and amplification are required for a rapid and effective homeostatic response. By integrating these two functions within a single molecular assembly, Neto-α ensures fast and efficient compensatory responses to perturbations. This evolutionarily conserved signaling module, Neto (or Neuropilin)/Sema/Plex/Abl, likely operates in cellular contexts beyond neural function, including in tumorigenesis.

LRRK2: Molecular Mechanisms in Parkinson’s Disease

Structural, biochemical, and cellular evidence is integrated to advance a unifying hypothesis that PD-associated LRRK2 dysfunction arises from maladaptive stabilization of specific conformational and spatial states within a membrane-responsive signalling network, leading to persistent misregulation of Rab-dependent trafficking and organelle homeostasis.