Biology subjects

Pilotto, F.

Publications and source records attributed to Pilotto, F..

3 recordsLinked to original sources

bioRxiv2026

TLR4-mediated neuroimmune signalling drives proprioceptive neuron degeneration in Friedreich ataxia

Friedreich ataxia (FA) is one of the most common inherited autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion in the FXN gene, leading to frataxin deficiency and progressive sensory and spinocerebellar ataxia. FA is characterized by selective vulnerability of proprioceptive sensory neurons (pSNs) in the dorsal root ganglia (DRG), which are major contributors to sensory ataxia. Despite the central role of mitochondrial dysfunction in FA, the mechanisms that drives the neuronal loss remains unclear. Here, we show that metabolic stress in sensory neurons elicits a neuroimmune response in surrounding tissue, revealing a non-cell-autonomous mechanism of disease progression. We identify Toll-like receptor 4 (TLR4) signaling as a key link between neuronal dysfunction and inflammatory response. Inhibition of TLR4 reduces cellular stress, restores neuronal integrity, and delays disease progression in vivo. These findings redefine FA as a disorder involving neuroimmune crosstalk and highlight TLR4 signaling as a potential therapeutic target.

neuroscience↗

bioRxiv2022

mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a devastating rare neurodevelopmental disease without a cure, caused by mutations of the serine/threonine kinase CDKL5 highly expressed in the forebrain. CDD is characterized by early-onset seizures, severe intellectual disabilities, autistic-like traits, sensorimotor and cortical visual impairments (CVI). The lack of an effective therapeutic strategy for CDD urgently demands the identification of novel druggable targets potentially relevant for CDD pathophysiology. To this aim, we studied metabotropic glutamate receptors 5 (mGluR5) for their important role in critical mechanisms involved in CDD, i.e.: synaptogenesis, dendritic spines formation/maturation and synaptic plasticity, and because mGluR5 function depends on the postsynaptic protein Homer1bc that is downregulated in the cerebral cortex of CDKL5-/y mice. In this study, we reveal that CDKL5 loss tampers with (i) the strength of Homer1bc-mGluR5 binding, (ii) the synaptic localization of mGluR5 and (iii) the mGluR5-mediated enhancement of NMDA-induced neuronal responses. Importantly, we showed that the stimulation of mGluR5 activity by administering in mice specific positive-allosteric-modulators, i.e.: 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) or RO6807794, corrected the synaptic, functional and behavioural defects shown by CDKL5-/y mice. Notably, the cerebral cortex of 2 CDD patients show similar changes in the synaptic organization to mutant CDKL5 mice, including a reduced mGluR5 expression, suggesting that mGluR5 represent a promising therapeutic target for CDD patients.

neuroscience↗

bioRxiv2020

CDNF rescues motor neurons in three animal models of ALS by targeting ER stress

The role of chronic endoplasmic reticulum (ER) stress in the pathophysiology of Amyotrophic lateral sclerosis (ALS), as well as a potential drug target, has received increasing attention. Here, we investigated the mode of action and therapeutic effect of the ER resident protein cerebral dopamine neurotrophic factor (CDNF) in preclinical models of ALS harboring different genetic mutations. We identify that intracerebroventricular (i.c.v.) administration of CDNF significantly halts the progression of the disease and improves motor behavior in TDP43-M337V and SOD1-G93A rodent models of ALS. CDNF rescues motor neurons (MNs) in vitro and in vivo from ER stress associated cell death and its beneficial effect is independent of genetic disease etiology. Notably, CDNF regulates the unfolded protein response (UPR) initiated by transducers IRE1, PERK, and ATF6, thereby enhancing MN survival. Thus, CDNF holds great promise for the design of new rational treatments for ALS.

neuroscience↗