Biology subjects

Di Iacovo, A.

Publications and source records attributed to Di Iacovo, A..

3 recordsLinked to original sources

bioRxiv2025

LRRK2 G2019S disrupts GABAergic signaling and shifts excitatory/inhibitory balance in the striatum

The excitatory/inhibitory (E/I) balance within neural circuits is essential for proper brain function, and its disruption is a hallmark of several neurodegenerative diseases. In Parkinsons disease (PD), widespread alterations in the basal ganglia circuitry lead to an E/I imbalance in the striatum, contributing to excitotoxicity. Leucine-rich repeat kinase 2 (LRRK2) has recently emerged as a key contributor to both familial and sporadic forms of PD, with the pathogenic Gly2019Ser (G2019S) mutation representing one of the most frequently observed variants. This mutation is known to exacerbate excitotoxicity by impairing glutamate reuptake mechanisms, particularly through dysregulation of EAAT2 activity and its membrane localization. In contrast, the role of LRRK2 in GABAergic transmission remains poorly understood. Here, we reveal a clear modulation of inhibitory signaling by LRRK2 through a comprehensive approach combining mouse striatal slices and Xenopus laevis oocytes. Our results demonstrate, for the first time, that LRRK2 G2019S induces a significant reduction in GABA-evoked current amplitudes. Moreover, we identified an altered distribution of receptor isoforms in pathological tissue, affecting both tonic and phasic GABA currents. Specifically, synaptic GABAA receptors containing the {gamma}2 subunit were functionally modulated by LRRK2 G2019S. The reduced availability of gephyrin in the presence of the G2019S variant may impair the gephyrin-GABAA receptor complex, leading to decreased receptor surface expression and further shifting the glutamate/GABA current ratio toward excitatory dominance. This is supported by the increased activity of AMPA and NMDA receptors observed in the pathological striatum. Overall, our findings highlight a previously underappreciated role of LRRK2 G2019S in impairing GABAergic transmission and disrupting the E/I balance. These insights point to novel circuit-level mechanisms underlying LRRK2-linked PD and suggest new avenues for the development of disease-modifying therapies targeting inhibitory dysfunction. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/684189v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1b685b3org.highwire.dtl.DTLVardef@3ea39org.highwire.dtl.DTLVardef@1064a58org.highwire.dtl.DTLVardef@1fb0304_HPS_FORMAT_FIGEXP M_FIG C_FIG The LRRK2 G2019S mutation contributes to excitatory/inhibitory imbalance by reducing GABA-evoked currents. Specifically, it is associated with diminished phasic GABAergic transmission and enhanced tonic inhibition, suggesting an altered subcellular distribution of GABAA receptor subtypes.

neuroscience↗

bioRxiv2025

Delineating plant responses to the 3',5'- and 2',3'-cAMP isomers

Similar to animals, both the 3,5- and the 2,3-cAMP isomers are present in plants. The former is the enzymatic product of adenylate cyclases (ACs), the latter is an RNA degradation product. While there is increasing evidence that both isomers can elicit or modulate a broad range of physiological responses, the question of isomer specificity of responses has remained largely unresolved. To delineate isomer-specific responses in Arabidopsis thaliana at the systems level, we have combined a comparative proteomics and electrophysiological approaches. Both isomers cause distinct systemic effects on the proteome, with the 2,3 isomer notably affecting systems-level functions like transcriptional regulation. None of the isomers affects net ion fluxes in the root under control conditions, but both were able to attenuate the magnitude of oxidative stress-induced K+ net loss and Ca2+ uptake by 2-fold. Isomer-specific responses of single molecular targets were assessed in the cyclic nucleotide-gated channels 2 and 18 (CNGC2 and CNGC18). Both channels are gated by the 3,5-cAMP isomer only, suggesting that the gating is isomer-specific and this implies that gating in vivo depends on catalytically active ACs. HighlightsDistinct Arabidopsis responses to 3,5- and 2,3-cAMP uncover isomer-specific molecular targets and physiological effects in cyclic nucleotide signaling.

plant biology↗

bioRxiv2021

Trafficking of the glutamate transporter is impaired in LRRK2-related Parkinson's disease

The Excitatory Amino Acid Transporter 2 (EAAT2) accounts for 80 % of brain glutamate clearance and is mainly expressed in astrocytic perisynaptic processes. EAAT2 function is finely regulated by endocytic events, recycling to the plasma membrane and degradation. Noteworthy, deficits in EAAT2 have been associated with neuronal excitotoxicity and neurodegeneration. In this study, we show that EAAT2 trafficking is impaired by the leucine-rich repeat kinase 2 (LRRK2) pathogenic variant G2019S, a common cause of late-onset familial Parkinsons disease (PD). In LRRK2 G2019S human brains and experimental animal models, EAAT2 protein levels are significantly decreased, which is associated with elevated gliosis. The decreased expression of the transporter correlates with its reduced functionality in mouse LRRK2 G2019S purified astrocytic terminals and in Xenopus laevis oocytes expressing human LRRK2 G2019S. In LRRK2 G2019S knockin mouse brain, the correct surface localization of the endogenous transporter is impaired, resulting in its interaction with a plethora of endo-vesicular proteins. Mechanistically, we report that pathogenic LRRK2 kinase activity delays the recycling of the transporter to the plasma membrane via Rabs inactivation, causing its intracellular relocalization and degradation. Taken together, our results demonstrate that pathogenic LRRK2 interferes with the physiology of EAAT2, pointing to extracellular glutamate overload as a possible contributor to neurodegeneration in PD.

neuroscience↗