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

Syntaxin-4 at the Crossroads of Synaptic Plasticity and Neurodegeneration: From Molecular Mechanisms to Biomarker and Therapeutic Potential.

Syntaxin-4 (Stx4), a member of the Qa-SNARE protein family, is a pivotal regulator of membrane trafficking. Stx4 is predominantly localized at the postsynaptic membrane of neurons and in glial cells, where it is essential for synaptic plasticity and the maintenance of neuronal homeostasis. Stx4 facilitates the activity-dependent exocytosis of glutamatergic receptors, thereby governing the balance between Long-Term Potentiation (LTP) and Long-Term Depression (LTD). Emerging evidence suggests that dysregulation of Stx4 is intricately linked to the pathogenesis of neurodegenerative diseases. In Alzheimer's disease, Stx4 is involved in synaptic dysfunction and cognitive impairment through its interactions with amyloid-β (Aβ) and tau pathologies, affecting receptor recruitment at dendritic spines. In Parkinson's Disease (PD), Stx4 contributes to α-synuclein proteostasis, dopaminergic signaling, neuroinflammation, and the maintenance of blood-brain barrier integrity. While its presence in cerebrospinal fluid highlights its potential as a candidate biomarker for these diseases, further validation is required to establish clinical utility. This review summarizes current mechanistic insights into Stx4's multifaceted roles in the neurodegenerative disorders and explores the therapeutic prospects of targeting Stx4-mediated pathways due to its translational potential.

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

The ARHGAP32 isoform PX-RICS is specifically targeted to inhibitory synapses by binding to gephyrin.

Gephyrin is identified as the primary synaptic anchor for PX-RICS and the N-terminal gephyrin-binding region (GBR) engages gephyrin E-domain through conserved hydrophobic interactions, explaining the isoform-specific targeting of PX-RICS (but not RICS) to inhibitory synapses.

α2δ-1 regulates synaptic AMPA receptor trafficking and LTP through distinct pre- and postsynaptic functions.

Activity-dependent trafficking of AMPA receptors (AMPARs) and subsequent long-term synaptic strengthening underlie different forms of learning and memory. The AMPAR subunit GluA1 amino-terminal domain (ATD, a. k. a. NTD) plays a critical role in synaptic AMPAR trafficking and LTP. The GluA1 ATD accounts for almost half the proteins' size and protrudes significantly into the synaptic cleft, hence it is ideally localized for interactions with synaptic cleft proteins. Using unbiased proteomics, we identified the epilepsy and intellectual disability-associated voltage-gated calcium channel (VGCC) auxiliary subunit α2δ-1 as a GluA1 ATD-interacting protein. At CA1 synapses, postsynaptic deletion of α2δ-1 selectively enhanced basal synaptic AMPAR, but not NMDAR currents. Conversely, presynaptic α2δ-1 deletion did not affect basal synaptic transmission but decreased LTP. α2δ-1 deletion in hippocampal field CA3 impaired performance in an object location memory task, but not other forms of memory. Collectively, our work identifies α2δ-1 as an extracellular AMPAR regulatory protein with distinct pre- and postsynaptic functions: in cis, limiting AMPAR access to synapses; in trans, facilitating LTP. Furthermore, it expands our understanding of the mechanisms underlying α2δ-1's regulation of hippocampal function and raise the possibility that α2δ-1-dependent AMPAR regulation may contribute to the effects of gabapentinoid drugs.

WNK-dependent phosphorylation of gephyrin tunes GABAA receptors at inhibitory synapses and modulates anxiety behavior.

The role of the chloride-sensitive kinase WNK1 and its effector SPAK in the brain remains poorly understood. Here, we identify a WNK-dependent regulatory mechanism that directly controls the synaptic diffusion and clustering of inhibitory GABAA receptors (GABAARs), as well as their membrane stability and endocytosis. We show that activation of WNK signaling stabilizes GABAARs at inhibitory synapses, while inhibition enhances receptor internalization. This regulation depends on the phosphorylation state of two residues in the central linker region of the gephyrin scaffold protein. Modulating WNK activity alters neuronal activity and the kinetics of GABAergic currents. In vivo, expression of a phospho-mimetic form of gephyrin at WNK-targeted sites produces anxiolytic-like effects. Together with prior evidence showing that WNK signaling regulates the chloride transporters KCC2 and NKCC1, key determinants of intracellular chloride homeostasis and GABAergic efficacy, our findings position the WNK pathway as a master regulator of inhibitory synapse function.

Loss of Atp8a2 drives neurodegeneration through the dysregulation of spatiotemporal phosphatidylserine externalization in mature neurons

Phosphatidylserine (PS) asymmetry in plasma membranes is critical for cellular functions and serves as an apoptotic signal in many cell types. However, in mature neurons, the molecular mechanisms governing PS distribution, its precise regulation, and its functional significance beyond apoptosis and development remain poorly understood — particularly in the context of neurodegeneration. Here, we mapped the spatiotemporal dynamics of PS exposure in mature hippocampal neurons under physiological and pathological conditions using time-lapse imaging, revealing specific PS externalization hotspots at dendritic branching points. Using multiple in vitro and in vivo neurodegeneration models combined with molecular modeling, RNA interference, pharmacological interventions, and biochemical assays, we identified Atp8a2 as the primary regulator of PS asymmetry in mature neurons beyond its known roles in development. Notably, Atp8a2 expression levels — rather than its flippase activity alone — were essential for maintaining neuronal structural integrity and viability. Atp8a2 expression was significantly altered by neurotoxic stimuli and in multiple mouse models of neurodegeneration. Reduced Atp8a2 expression led to increased PS exposure, compromised neuronal architecture, and heightened susceptibility to degeneration, whereas Atp8a2 overexpression conferred substantial neuroprotection. The distinction between Atp8a2’s enzymatic activity and expression level reveals a mechanism of neuronal homeostasis linking PS regulation to structural integrity and survival, possibly through association with cytoskeletal protein networks. Thus, Atp8a2 expression is a critical determinant of mature neuronal viability, presenting a potential target for neuroprotective strategies in neurodegeneration.