Biology subjects

Perrone-Bizzozero, N.

Publications and source records attributed to Perrone-Bizzozero, N..

6 recordsLinked to original sources

bioRxiv2025

An axon-intrinsic loop restricts nerve regeneration through axonal protein synthesis

Injured axons synthesize the RNA Binding Protein KHSRP that promotes mRNA decay and slows nerve regeneration. Axotomy-induced increase in axoplasmic Ca2+ activates axonal Khsrp translation, and while Ca2+ returns to pre-injury levels within 16 hours post-axotomy, axonal KHSRP remains elevated. Alternating translation of Reg3a and Khsrp sustains axonal KHSRP levels in regenerating axons. Nerve injury activates Reg3a expression, resulting in increased REG3A synthesis and secretion from axons. REG3A stimulates ER Ca2+ release to activate PERK, increase eIF2 phosphorylation, and increase Khsrp translation. Axoplasmic Ca2+ slowly oscillates in growth cones and Reg3A depletion attenuates growth cone Ca2+ oscillations, decreases KHSRP synthesis, reduces the axons retractive events, and accelerates peripheral nerve regeneration. Thus, REG3A to KHSRP signaling provides an axon-intrinsic loop that decelerates axon growth through localized mRNA translation.

neuroscience↗

bioRxiv2025

KHSRP-mediated Decay of Axonally Localized Prenyl-Cdc42 mRNA Slows Nerve Regeneration

The small GTPase CDC42 promotes axon growth through actin filament polymerization and this growth is driven by axonal localization of the mRNA encoding the prenylated CDC42 isoform (Prenyl-Cdc42). Here, we show that axonal Prenyl-Cdc42 mRNA transport and translation are decreased by growth-inhibiting stimulation and increased by growth-promoting stimulation. In contrast, axonal RhoA mRNA transport and translation are increased by growth inhibition but unaffected by growth promotion. Localized increase in KHSRP in response to growth inhibitory stimulation, through elevation of intracellular Ca2+, promotes decay of axonal Prenyl-Cdc42 mRNA. Distinct 3UTR motifs regulate transport and stability of axonal Prenyl-Cdc42 mRNA. KHSRP protein binds to a Prenyl-Cdc42 mRNA motif within nt 801-875 and the mRNA is remarkably increased in axons of Khsrp-/- mice. Selective depletion of Prenyl-Cdc42 mRNA from axons reverses the accelerated axon regeneration seen in Khsrp-/-mice.

neuroscience↗

bioRxiv2023

Association between the oral microbiome and brain resting state connectivity in schizophrenia

Recent microbiome-brain axis findings have shown evidence of the modulation of microbiome community as an environmental mediator in brain function and psychiatric illness. This work is focused on the role of the microbiome in understanding a rarely investigated environmental involvement in schizophrenia (SZ), especially in relation to brain circuit dysfunction. We leveraged high throughput microbial 16s rRNA sequencing and functional neuroimaging techniques to enable the delineation of microbiome-brain network links in SZ. N=213 SZ and healthy control (HC) subjects were assessed for the oral microbiome. Among them, 139 subjects were scanned by resting-state functional magnetic resonance imaging (rsfMRI) to derive brain functional connectivity. We found a significant microbiome compositional shift in SZ beta diversity (weighted UniFrac distance, p= 6x10-3; Bray-Curtis distance p = 0.021). Fourteen microbial species involving pro-inflammatory and neurotransmitter signaling and H2S production, showed significant abundance alterations in SZ. Multivariate analysis revealed one pair of microbial and functional connectivity components showing a significant correlation of 0.46. Thirty five percent of microbial species and 87.8% of brain functional network connectivity from each component also showed significant differences between SZ and HC with strong performance in classifying SZ from HC, with an area under curve (AUC) = 0.84 and 0.87, respectively. The results suggest a potential link between oral microbiome dysbiosis and brain functional connectivity alteration in relation to SZ, possibly through immunological and neurotransmitter signaling pathways and the hypothalamic-pituitary-adrenal axis, supporting for future work in characterizing the role of oral microbiome in mediating effects on SZ brain functional activity.

microbiology↗

bioRxiv2020

Intra-axonal translation of Khsrp mRNA slows axon regeneration by destabilizing localized mRNAs

Proteins generated by localized mRNA translation in axons support nerve regeneration through retrograde injury signaling and localized axon growth mechanisms. RNA binding proteins (RBP) are needed for this and other aspects of post-transcriptional control of localized mRNAs, but only a limited number of axonal RBPs have been reported. We used a targeted mass spectrometry approach to profile the axonal RBPs in naive, injured and regenerating PNS axons. We detected 76 axonal proteins that are reported to have RNA binding activity, with the levels of several of these axonal RBPs changing with axonal injury and regeneration. These axonal RBPs with altered axoplasm levels include KHSRP that we previously reported decreases neurite outgrowth in developing CNS neurons. We show that KHSRP levels rapidly increase in sciatic nerve axons after crush injury and remain elevated increasing in levels out to 28 days post-sciatic nerve crush injury. Khsrp mRNA localizes into axons and the rapid increase in axonal KHSRP after axotomy is mediated by the local translation of its mRNA. KHSRP binds to mRNAs with a 3UTR AU-rich element and targets those mRNAs to the cytoplasmic exosome for degradation. KHSRP knockout mice show increased axonal levels of defined KHSRP target mRNAs, Gap43 and Snap25 mRNAs, following sciatic nerve injury and accelerated nerve regeneration in vivo. These data indicate that axonal translation of Khsrp mRNA following nerve injury serves to destabilize other axonal mRNAs and slow axon regeneration.

neuroscience↗

bioRxiv2020

Loss of KHSRP Increases Neuronal Growth and Synaptic Transmission and Alters Memory Consolidation Through RNA Stabilization

The KH-type splicing regulatory protein (KHSRP) is an RNA-binding protein linked to decay of AU-rich element containing mRNAs. We have previously shown that KHSRP destabilizes the mRNA encoding the growth-associated protein GAP-43 and decreases neurite growth in cultured embryonic neurons. In contrast, loss of KHSRP stabilizes Gap43 mRNA and increases neurite growth. Here, we have tested functions of neural KHSRP in vivo. We find upregulation of 1460 mRNAs in the neocortex of adult Khsrp-/- mice, of which 527 bind to KHSRP with high specificity. These KHSRP targets are involved in pathways for neuronal morphology, axon guidance, neurotransmission and long-term memory. Neocortical neurons show increased axon growth and dendritic spine density in Khsrp-/- mice. Analyses of neuronal cultures from embryonic Khsrp-/- mice point to a neuron-intrinsic alteration in axonal and dendritic growth and elevations in KHSRP-target mRNAs, including subcellularly localized mRNAs. Hippocampus and infralimbic cortex of Khsrp-/- mice show presynaptic elevations in neurotransmission. The Khsrp-/- mice have significant deficits in both trace conditioning and attention set-shifting tasks compared Khsrp+/+ mice, indicating impaired prefrontal- and hippocampal-dependent memory consolidation with loss of KHSRP. Overall, our results indicate that prenatal deletion of KHSRP impairs neuronal development resulting in alterations in neuronal morphology and function by changing post-transcriptional control of neuronal gene expression.

neuroscience↗

bioRxiv2018

Network modules linking expression and methylation in prefrontal cortex of schizophrenia

Tremendous work has demonstrated the critical roles of genetics, epigenetics as well as their interplay in brain transcriptional regulations in the pathology of schizophrenia (SCZ). There is great success currently in the dissection of the genetic components underlying risk-conferring transcriptomic networks. However, the study of regulating effect of epigenetics, as a modulator of environmental factors, in the etiopathogenesis of SCZ still faces many challenges. In this work we investigated DNA methylation and gene expression from the dorsolateral prefrontal cortex (DLPFC) region of schizophrenia patients and healthy controls using weighted correlation network approaches. We identified and replicated two expression and two methylation modules significantly associated with SCZ. Among them, one pair of expression and methylation modules were significantly overlapped in the module genes which were enriched in astrocyte-associated functional pathways, and specifically expressed in astrocytes. Another two linked expression-methylation module pairs were involved aging process with module genes mostly related to oligodendrocyte development and myelination, and specially expressed in oligodendrocytes. Further examination of underlying quantitative trait loci (QTLs) showed significant enrichment in genetic risk of most psychiatric disorders for expression QTLs but not for methylation QTLs. These results support the coherence between methylation and gene expression in a network level, and suggest a combinatorial effect of genetics and epigenetics in regulating gene expression networks specific to glia cells in relation with SCZ and aging process.

neuroscience↗