Biology subjects

Ledonne, A.

Publications and source records attributed to Ledonne, A..

3 recordsLinked to original sources

bioRxiv2025

Sex-dimorphic effects of neuromelanin buildup in rodent nigral dopamine neurons: implications for sex-biased vulnerability in Parkinson's disease

Neuromelanin (NM) is a dark pigment accumulating with age in human substantia nigra pars compacta (SNpc) dopamine (DA) neurons, conferring the dark look that inspired nigral areas name. Despite NM has long been associated with Parkinsons disease (PD), as melanized neurons favorably degenerate during disease development, NM functions within SNpc DA neurons are still mostly elusive. Here, by exploiting an NM-producing rat model generated by viral vector-induced expression of human Tyrosinase (hTyr), we inspected NM impact on nigral DA neurons survival and activity, on mitochondrial functionality of SNpc, and behaviors resembling non-motor and motor PD symptoms. Our data reveal sex dimorphism in NM effects on nigrostriatal dopamine circuit, with sex-biased alterations in neuronal firing activity and underlying intrinsic currents, nigral mitochondrial functions, and non-motor PD symptoms (anxiety). In conclusion, this study discloses unrealized NM effects within nigral DA neurons, advancing our comprehension of sex-specific features shaping sex-biased vulnerability to PD.

neuroscience↗

bioRxiv2024

ErbB inhibition rescues nigral dopamine neuron hyperactivity and repetitive behaviors in a mouse model of fragile X syndrome

Repetitive behaviors are core symptoms of autism spectrum disorders (ASD) and fragile X syndrome (FXS), the prevalent genetic cause of intellectual disability and autism. The nigrostriatal dopamine (DA) circuit rules movement and habit formation; therefore, its dysregulation stands as a leading substrate for repetitive behaviors. However, beyond indirect evidence, specific assessment of nigral DA neuron activity in ASD and FXS models is lacking. Here, we show that hyperactivity of substantia nigra pars compacta (SNpc) DA neurons is an early feature of FXS. The underlying mechanisms rely on mGluR1 and ErbB receptors. Up-regulation of ErbB4 and ErbB2 in nigral DA neurons drives neuronal hyperactivity and repetitive behaviors of the FXS mouse, simultaneously rescued by ErbB inhibition. In conclusion, beyond providing the first evidence of dysregulation of the SNpc DA nucleus in FXS, we identify novel targets - ErbB receptors - whose inhibition proficiently attenuates repetitive behaviors, thus opening an avenue toward innovative therapies for ASD and FXS.

neuroscience↗

bioRxiv2024

Systemic inflammation triggers long-lasting neuroinflammation and accelerates neurodegeneration in a rat model of Parkinson's disease overexpressing human alpha-synuclein

Increasing efforts have been made to elucidate how genetic and environmental factors interact in Parkinsons disease (PD). In the present study, we assessed the development of symptoms on a genetic PD rat model that overexpresses human -synuclein (Snca+/+) at a presymptomatic age, exposed to a pro-inflammatory insult by intraperitoneal injection of lipopolysaccharide (LPS), using immunohistology, high-dimensional flow cytometry, constant potential amperometry, and behavioral analyses. A single injection of LPS into WT and Snca+/+ rats triggered long-lasting increase in the activation of pro-inflammatory microglial markers, monocytes, and T lymphocytes. However, only LPS Snca+/+ rats showed dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), associated with a reduction in the release of evoked dopamine in the striatum. No significant changes were observed in the behavioral domain. We propose our double-hit animal as a reliable model to investigate the mechanisms whereby -synuclein and inflammation interact to promote neurodegeneration in PD.

neuroscience↗