Biology subjects

Martello, A.

Publications and source records attributed to Martello, A..

5 recordsLinked to original sources

bioRxiv2025

N-Acetyl-l-Leucine (NALL) rescues inter-organelle communication in Niemann-Pick disease type-C patient cells.

Niemann-Pick disease type-C (NPC) is a progressive neurodegenerative disease caused by loss-of-function mutations in NPC1 or NPC2. In NPC patient cells lacking functional NPC proteins, lipids accumulate in lysosomes causing severe lysosomal storage disease. Surprisingly, lipid accumulation caused by defects in the lysosomal membrane protein NPC1 is strongly associated with mitochondrial dysfunction. The mechanism of this coupled dysfunction is not fully understood, but a recently approved NPC therapeutic, N-Acetyl-l-Leucine (NALL), reverses both lysosomal and mitochondrial phenotypes in NPC patient cells. Our data indicate that direct inter-organelle communication through lysosome membrane contact sites with mitochondria contribute to the coupled organelle dysfunction in NPC. We find that mitochondria:lysosome contact sites are expanded in NPC, dependent on accumulation of lysosomal cholesterol and that NALL rescues the aberrant contact sites. We further identify a direct correlation between mitochondria:lysosome contact site expansion and mitochondrial dysfunction and propose that normalisation of contacts sites contributes to the coupled restoration of lysosome and mitochondrial function by NALL. We further find that NALL-mediated normalisation of lysosomal contact sites also correlates with restoration of autophagic flux and lysosome repair in NPC patient cells.

cell biology↗

bioRxiv2025

Altered cortical network in Parkinson's Disease: the central role of PV interneuron and synaptic remodelling

Parkinson's disease (PD) is traditionally defined by the progressive degeneration of nigrostriatal dopaminergic neurons; however, accumulating evidence highlights extensive cortical dysfunctions as key contributors to motor and non-motor symptoms. Despite this growing recognition, the precise mechanisms underlying cortical network disruptions and their contribution to PD pathophysiology remain poorly understood, particularly in relation to parvalbumin-positive interneurons (PV-INs) and maladaptive plasticity. Here, we investigate the dysregulation of cortical network homeostasis in PD using a 6-hydroxydopamine (6-OHDA) mouse model, focusing on the progressive disruption of parvalbumin-positive interneuron (PV-IN) connectivity, excitatory/inhibitory balance, and neuroinflammatory responses. Using a multimodal approach integrating longitudinal electrophysiology, wide-field calcium imaging, and histological analyses, we revealed striking alterations in cortical activity and connectivity. Specifically, we observed pathological high-gamma hyperactivity during movement, accompanied by severe disruptions in PV-IN connectivity across motor and somatosensory cortices. Histological analyses further revealed synaptic imbalances and microglial dysregulation, suggesting an extensive cortical response to dopaminergic loss. These findings indicate that PV-IN dysfunction drives cortical maladaptive plasticity, leading to network desynchronization and motor deficits. By reframing PD as a disorder of cortical network homeostasis, this study provides novel mechanistic insights and identifies cortical plasticity as a promising therapeutic target for disease modification.

neuroscience↗

bioRxiv2024

Combining Gamma Neuromodulation and Robotic Rehabilitation Restores Parvalbimin-mediated Gamma Function and Boosts Motor Recovery in Stroke Mice

Stroke is a leading cause of long-term disability, often characterized by compromised motor function. Gamma band is known to be related to Parvalbumin interneurons (PV-IN) synchronous discharge and it has been found to be affected after stroke in humans and animals. Both Gamma band and PV-IN also play a key role in motor function, thus representing a promising target for post-stroke neurorehabilitation. Non-Invasive neuromodulatory approaches are considered a safe intervention and can be used for this purpose. This study presents a novel, clinically relevant, non-invasive and well-tolerated sub-acute treatment combining robotic rehabilitation with advanced neuromodulation techniques, validated in a mouse model of ischemic injury. In the sub-acute phase after stroke, we scored profound deficits in motor-related Gamma band regulation on the perilesional cortex. Accordingly, both at the perilesional and at the whole-cortex levels, the damage results in impaired PV-IN activity, with reduced firing rate and increased functional connectivity levels. Therefore, we tested the therapeutic potential of coupling robotic rehabilitation with optogenetic PV-driven Gamma band stimulation in a subacute post-stroke phase during motor training to reinforce the efficacy of the treatment. Frequency-specific movement-related Gamma band stimulation, when combined with physical training, significantly improved forelimb motor function. More importantly, by pairing robotic rehabilitation with a clinical-like non-invasive 40 Hz transcranial Alternating Current Stimulation, we achieved similar motor improvements mediated by the effective restoring of movement-related Gamma band power and increased PV-IN connections in premotor cortex. Our research introduces a new understanding of the role of parvalbumin-interneurons in post-stroke impairment and recovery. These results highlight the synergistic potential of combining perilesional Gamma band stimulation with robotic rehabilitation as a promising and realistic therapeutic approach for stroke patients. SummaryStroke-induced motor deficits are accompanied by alteration of Gamma modulation and PV-interneurons activity and restored by a combination of non-invasive Gamma stimulation and robotic therapy.

neuroscience↗

bioRxiv2024

Age-dependent cortical overconnectivity revers under anesthesia in Shank3 mice

Growing evidence points to brain network dysfunction as a central neurobiological basis for autism spectrum disorders (ASDs). As a result, studies on Functional Connectivity (FC) have become pivotal for understanding the large-scale network alterations associated with ASD. Despite ASD being a neurodevelopmental disorder, and FC being significantly influenced by the brain state, existing FC studies in mouse models predominantly focus on adult subjects under anesthesia. The differential impact of anesthesia and age on cortical functional networks in ASD subjects remains unexplored. To fill this gap, we conducted a longitudinal evaluation of FC across three brain states and three ages in the Shank3b mouse model of autism. We utilized wide-field calcium imaging to monitor cortical activity in Shank3b+/- and Shank3b+/+ mice fromlate development (P45) through adulthood (P90), and isoflurane anesthesia to manipulate the brain state. Our findings reveal that network hyperconnectivity, emerging from the barrel-field cortices during the juvenile stage, progressively expands to encompass the entire dorsal cortex in adult Shank3b+/- mice. Notably, the severity of FC imbalance is highly dependent on the brain state: network alterations are more pronounced in the awake state and shift towards hypoconnectivity under anesthesia. These results underscore the crucial role of anesthesia in detecting autism-related FC alterations and identify a significant network of early cortical dysfunction associated with autism. This network represents a potential target for non-invasive translational treatments.

neuroscience↗

bioRxiv2019

Trichoplein controls endothelial cell function by regulating autophagy

Autophagy is an essential cellular quality control process that emerged critical for vascular homeostasis. Here we describe, the role for Trichoplein (TCHP) protein in linking autophagy with endothelial cells (ECs) function. The depletion of TCHP in ECs impairs migration and sprouting. TCHP directly binds PCM1, to regulate degradation of GABARAP, thus leading to a defective autophagy. Mechanistically, TCHP is indispensable for autophagosome maturation and its depletion resulted in the accumulation of SQSTM1/p62 (p62) and unfolded protein aggregates in ECs. The latter process is coupled to TCHP-mediated NF-kB activation. Of note, low levels of TCHP and high p62 levels were detected in primary ECs from patients with coronary artery disease. In addition, Tchp knock-out mice showed accumulation of p62 in the heart and cardiac vessels and reduced cardiac vascularization. Here, we reveal an autophagy-mediated mechanism for TCHP down-regulation, which poses a plausible target for regulation of endothelial function.

molecular biology↗