Biology subjects

Marullo, C.

Publications and source records attributed to Marullo, C..

2 recordsLinked to original sources

bioRxiv2024

Altered calcium responses and antioxidant properties in Friedreich's ataxia-like cerebellar astrocytes

Friedreichs ataxia (FRDA) is a neurodegenerative disorder characterized by severe neurological signs affecting both the peripheral and central nervous system, caused by reduced levels of the frataxin protein (FXN). While several studies highlight cellular dysfunctions in neurons and various other cell types, there is limited information on the effects of FXN depletion in astrocytes and on the potential non-cell autonomous mechanisms affecting neurons in FRDA. In this study, we generated a model of FRDA cerebellar astrocytes to unveil phenotypic alterations that might contribute to cerebellar atrophy and the degeneration of glutamatergic neurons observed in cerebellar dentate nuclei. We treated primary cerebellar astrocytes with an RNA interference-based approach, to achieve a reduction of FXN comparable to that observed in patients. These FRDA-like astrocytes display some typical features of the disease, such as an increase of oxidative stress, as well as specific functional alterations. Notably, cerebellar astrocytes deplete their reduced glutathione content, becoming more susceptible to oxidative insults. Moreover, FRDA-like astrocytes exhibit alterations of calcium homeostasis, with a reduction in calcium content in the intracellular stores and a corresponding change of calcium responses to purinergic stimuli. Our findings shed light on cellular changes caused by FXN downregulation in cerebellar astrocytes, which can interfere with their physiological and complex interaction with neurons. The potentially impaired ability to provide neuronal cells with glutathione or to release neuromodulators and bioactive molecules in a calcium-dependent manner could impact neuronal function and contribute to neurodegeneration.

cell biology↗

bioRxiv2023

Two neuronal models of TDP-43 proteinopathy display reduced axonal translation, increased oxidative stress, and defective exocytosis.

Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neurodegenerative disease mostly affecting people around 50-60 years of age. TDP-43, a ubiquitously expressed RNA-binding protein involved in pre-mRNA splicing and controlling mRNA stability and translation, forms neuronal cytoplasmic inclusions in an overwhelming majority of ALS patients, of both sporadic and familial origin, a phenomenon referred to as TDP-43 proteinopathy. These cytoplasmic aggregates disrupt the subcellular transport and localization of mRNA. The axon, like dendrites, is a site of mRNA translation, permitting the local synthesis of selected proteins, both constitutively and in response to stimuli reaching the axon and presynaptic terminal. This is especially relevant in upper and lower motor neurons, whose axon spans long distances, likely accentuating their susceptibility to ALS-related noxae. In this work we have generated and characterized two models of TDP-43 proteinopathy, consisting of virtually pure populations of mouse cortical neurons expressing a human TDP-43 fusion protein, wt or mutant, which accumulates as cytoplasmic aggregates. Neurons expressing human TDP-43 exhibit a global impairment in axonal protein synthesis, an increase in oxidative stress, and defects in presynaptic function and electrical activity. These changes correlate with deregulation in the axonal levels of polysome-engaged mRNAs playing relevant roles in those processes. Our data support the emerging notion that deregulation of mRNA metabolism and of axonal mRNA transport may trigger the dying-back neuropathy that initiates motor neuron degeneration in ALS.

neuroscience↗