Biology subjects

Puccio, H.

Publications and source records attributed to Puccio, H..

4 recordsLinked to original sources

bioRxiv2024

Frataxin deficiency in proprioceptive neurons is causal to inflammatory and glial responses in dorsal root ganglia

Friedreich ataxia (FA), the most common recessive hereditary ataxia, is an early-onset neurodegenerative disease characterized by pathological changes occurring first in the peripheral dorsal root ganglia (DRG), with loss of the large sensory proprioceptive neurons, leading to ganglionopathy and proprioceptive deficits. FA is caused by a mutation in frataxin gene (Fxn), leading to reduced expression of frataxin protein (FXN), an essential ubiquitous mitochondrial protein. Most research has focused on the pathophysiological involvement of proprioceptors. However, in recent years, neuroinflammation is increasingly recognized as an integral and critical contributor in FA pathogenesis. Furthermore, it has also recently been shown a primary reactivity of satellite glial cells (SGCs; glia tightly enwrapping proprioceptor cell bodies), suggesting a role of inflammation and SGC responses in the destruction of proprioceptors in FA patients DRGs. It remains unclear to what extent the increase in DRG macrophage response and/or SGC reactivity may contribute to FA phenotype. Therefore, it is important to fully study and understand the mechanism of proprioceptor-macrophages-SGC interactions and their regulations. Exploring relationship between these three cell types has profound implications for breaking through the limitation of treatment of FA. Here we asked whether FXN deficiency selectively in DRG proprioceptive neurons is sufficient to cause inflammatory and glial responses found in patients DRG. We used RNA profiling, bioinformatics signaling network and pathway analysis, combined with immunohistochemistry and behavioral experiments to reveal some genes, signaling pathways in macrophages and SGCs that may represent potential biomarkers of the disease. Our study revealed that proprioceptor FXN deficiency causes major changes in inflammatory macrophage and SGC gene transcription as well as macrophage and SGC number, highlighting molecular and cellular pathways that were sequentially altered, thus representing temporal signatures of FA ganglionopathy progression.

neuroscience↗

bioRxiv2023

Comparative multi-omics analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency

Cardiomyopathy is often fatal in Friedreich Ataxia (FA). However, the FA heart maintains adequate function until disease end stage, suggesting that it can initially adapt to the loss of frataxin (FXN). Conditional knockout mouse models with no Fxn expression show transcriptional and metabolic profiles of cardiomyopathy and mitochondrial integrated stress response (ISRmt). However, ISRmt has not been investigated in models with disease-relevant, partial decrease of FXN. We characterized the heart transcriptomes and metabolomes of three mouse models of partial FXN loss, YG8-800, KIKO-700, and FxnG127V. Few metabolites were significantly changed in YG8-800 mice and did not provide a signature of cardiomyopathy or ISRmt. Instead, several metabolites were altered in FxnG127V and KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FxnG127V hearts. However, these changes were surprisingly mild even at an advanced age (18-months), despite a severe decrease in FXN levels to 1% of WT. These findings indicate that the mouse heart has extremely low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy. Summary statementThe mitochondrial integrated stress response in the heart of a Friedreich Ataxia mouse model is surprisingly mild, despite a severe decrease in frataxin levels below 1% of normal.

molecular biology↗

bioRxiv2022

Epidermal maintenance of Langerhans cells relies on autophagy-regulated lipid metabolism

Macroautophagy (often-named autophagy), a catabolic process involving autophagy-related (Atg) genes, prevents accumulation of harmful cytoplasmic components and mobilizes energy reserves in long-lived and self-renewing cells. Autophagy deficiency affects antigen presentation in conventional dendritic cells (DCs) without impacting their survival. However, previous studies did not address epidermal Langerhans cells (LCs). Here, we demonstrate that deletion of either Atg5 or Atg7 in LCs leads to their gradual depletion. ATG5-deficient LCs showed metabolic dysregulation and accumulated neutral lipids. Despite increased mitochondrial respiratory capacity, they were unable to process lipids, eventually leading them to ferroptosis. Finally, metabolically impaired LCs upregulated proinflammatory transcripts and showed decreased expression of neuronal interaction receptors. Altogether, autophagy represents a critical regulator of lipid storage and metabolism in LCs, allowing their maintenance in the epidermis.

immunology↗

bioRxiv2020

High levels of frataxin overexpression leads to mitochondrial and cardiac toxicity in mouse models

Friedreich ataxia (FA) is currently an incurable inherited mitochondrial disease caused by reduced levels of frataxin (FXN). Cardiac dysfunction is the main cause of premature death in FA. AAV-mediated gene therapy constitutes a promising approach for FA, as demonstrated in cardiac and neurological mouse models. While the minimal therapeutic level of FXN protein to be restored and biodistribution have recently been defined for the heart, it is unclear if FXN overexpression could be harmful. Indeed, depending on the vector delivery route and dose administrated, the resulting FXN protein level could reach very high levels in the heart, cerebellum, or in off-target organs such as the liver. The present study demonstrates safety of FXN cardiac overexpression up to 9-fold the normal endogenous level, but significant toxicity to the mitochondria and heart above 20-fold. We show gradual severity with increasing FXN overexpression, ranging from subclinical cardiotoxicity to left ventricle dysfunction. This appears to be driven by impairment of mitochondria respiratory chain, ultrastructure and homeostasis, which lead to myofilaments alteration, cell death and fibrosis. Overall, this study underlines the need, during the development of gene therapy approaches, to consider appropriately vector potency, long term safety and biomarkers to monitor such events.

bioengineering↗