Biology subjects

Cima-Omori, M.-S.

Publications and source records attributed to Cima-Omori, M.-S..

4 recordsLinked to original sources

bioRxiv2026

Multivalent Tau-Fyn interactions cooperatively arrest postsynaptic density condensate dynamics

Tau-Fyn signaling at postsynaptic sites is implicated in synaptic dysfunction and neuronal hyperexcitability in Alzheimers disease and related tauopathies, yet the molecular mechanisms by which Tau-Fyn interactions influence postsynaptic signaling assemblies remain poorly understood. Here, we reconstitute biomolecular condensates and membrane-associated assemblies that mimic the postsynaptic density (PSD) to investigate how Tau and Fyn regulate PSD organization and dynamics. We show that Tau and Fyn co-partition into PSD condensates and N-methyl D-aspartate receptor subtype 2B (NR2B)-associated PSD clusters, with both proteins preferentially enriching in the condensed phase relative to core PSD scaffold proteins. Enrichment of Fyn within PSD condensates is recapitulated by an SH3-SH2 fragment lacking the kinase domain, indicating that the kinase domain is dispensable for condensate partitioning. Fluorescence recovery after photobleaching reveals that Tau markedly reduces Fyn mobility and, together with Fyn, cooperatively drives a pronounced dynamic arrest of PSD condensate components, including the central scaffold protein PSD-95. Disruption of a major Tau-Fyn interaction hotspot by P216A/P219A mutations in Tau nearly completely restores the mobility of both Fyn and PSD-95, demonstrating that cooperative Tau-Fyn interactions are required for dynamic arrest. NMR spectroscopy identifies a multivalent interaction network between the Tau proline-rich region and the Fyn SH3 domain involving multiple binding motifs, with residues P216 and P219 acting as major interaction determinants. A 1.4 [A] crystal structure of the Fyn SH3 domain bound to a Tau peptide reveals a ternary 2:1 Fyn:Tau assembly, providing structural support for multivalent Tau- Fyn engagement. Together, our findings establish a condensate-based mechanism by which multivalent Tau-Fyn interactions cooperatively regulate PSD condensate dynamics and provide a molecular framework linking Tau-Fyn signaling to synaptic dysfunction in tauopathies.

biochemistry↗

bioRxiv2024

Knockout of the LRRK2-counteracting RAB phosphatase PPM1H disrupts axonal autophagy and exacerbates alpha-synuclein aggregation

Parkinson disease-causing mutations in the LRRK2 gene hyperactivate LRRK2 kinase activity, leading to increased phosphorylation of a subset of RAB GTPases, which are master regulators of intracellular trafficking. In neurons, processive retrograde transport of autophagosomes is essential for autophagosome maturation and effective degradation of autophagosomal cargo in the axon. We found that knockout of the LRRK2-counteracting RAB phosphatase PPM1H resulted in a gene dose-dependent disruption of the axonal transport of autophagosomes, leading to impaired degradation of axonal alpha-synuclein (aSyn), a key protein in Parkinson disease pathophysiology. Defective autophagosome transport and impaired aSyn degradation also correlated with increased aSyn aggregation in primary PPM1H knockout neurons exposed to preformed fibrils of aSyn, an effect that was dependent on LRRK2 kinase activity. Thus, our results link LRRK2-mediated RAB hyperphosphorylation to aSyn pathology in Parkinson disease and further establish a role for impaired autophagy in Parkinson disease pathophysiology.

neuroscience↗

bioRxiv2022

Contributions of the N-terminal intrinsically disordered region of the SARS-CoV-2 nucleocapsid protein to RNA-induced phase separation

SARS-CoV-2 nucleocapsid protein is an essential structural component of mature virions, encapsulating the genomic RNA and modulating RNA transcription and replication. Several of its activities might be associated with the proteins ability to undergo liquid-liquid phase separation. NSARS-CoV-2 contains an intrinsically disordered region at its N-terminus (NTE) that can be phosphorylated and is affected by disease-relevant mutations. Here we show that NTE deletion decreases the range of RNA concentrations that can induce phase separation of NSARS-CoV-2. In addition, deletion of the prion-like NTE allows NSARS-CoV-2 droplets to retain their liquid-like nature during incubation. We further demonstrate that RNA-binding engages multiple parts of the NTE and changes NTEs structural properties. The results form the foundation to characterize the impact of N-terminal mutations and post-translational modifications on the molecular properties of the SARS-CoV-2 nucleocapsid protein. StatementThe nucleocapsid protein of SARS-CoV-2 plays an important role in both genome packaging and viral replication upon host infection. Replication has been associated with RNA-induced liquid-liquid phase separation of the nucleocapsid protein. We present insights into the role of the N-terminal part of the nucleocapsid protein in the proteins RNA-mediated liquid-liquid phase separation.

biophysics↗

bioRxiv2020

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Parkinsons disease (PD) and Alzheimers disease (AD) are common neurodegenerative disorders of the elderly and, therefore, affect a growing number of patients worldwide. Both diseases share, as a common hallmark, the accumulation of characteristic protein aggregates, known as Lewy bodies (LB) in PD, and neurofibrillary tangles in AD. LBs are primarily composed of misfolded -synuclein (aSyn), and neurofibrillary tangles are primarily composed of tau protein. Importantly, upon pathological evaluation, most AD and PD/Lewy body dementia cases exhibit mixed pathology, with the co-occurrence of both Lewy bodies and neurofibrillary tangles, among other protein inclusions. Recent studies suggest that both aSyn and tau pathology can spread and propagate through neuronal connections. Therefore, it is important to investigate the mechanisms underlying aggregation and propagation of these proteins for the development of novel therapeutic strategies. Here, we assessed the effects of different pharmacological interventions on the aggregation and internalization of tau and aSyn. We found that anle138b and epigallocatechin gallate decrease aSyn aggregation, that fulvic acid attenuates aggregation of the repeat domain of tau, and that dynasore reduces tau internalization. Establishing the effects of small molecules with different chemical properties on the aggregation and spreading of aSyn and tau will be important for the development of future therapeutic interventions.

neuroscience↗