Biology subjects

Marrocco, E.

Publications and source records attributed to Marrocco, E..

3 recordsLinked to original sources

bioRxiv2023

DNA actively contributes to gene expression of paired transcription factors.

The binding affinity of transcription factors (TFs) for their cognate DNA sequences controls gene expression. DNA determines the recruitment and positioning of TFs; whether it plays other roles is unknown. Here we found that the specific 22-bp sequence interposed between the CRX and NRL TFs in the proximal promoter of RHODOPSIN (RHO) largely controls the expression levels of RHO. Mutagenesis of this DNA-linker sequence resulted in wide variation in gene expression. In contrast, reciprocal exchange of human and murine RHO elements conferred species-specific expression levels. Targeting the DNA-linker with equal orthogonal DNA-binding proteins activates or represses RHO expression depending on its orientation relative to CRX and NRL binding sites. We conclude that DNA itself adds to TF activity through a code that determines optimal levels of RHO expression.

genetics↗

bioRxiv2020

Gene replacement therapy provides benefit in an adult mouse model of Leigh syndrome

Mutations in nuclear-encoded mitochondrial genes are responsible for a broad spectrum of disorders among which Leigh syndrome (LS) is the most common in infancy. No effective therapies are available for this severe disease mainly because of the limited capabilities of the standard adeno-associated viral (AAV) vectors to transduce both peripheral organs and the central nervous system (CNS) when injected systemically in adults. Here, we used the brain-penetrating AAV-PHP.B vector to reinstate gene expression in the Ndufs4 KO mouse model of LS. Intravenous delivery of an AAV.PHP.B-Ndufs4 vector in 1-month old KO mice restored mitochondrial complex I activity in several organs including the CNS. This gene replacement strategy extended lifespan, rescued metabolic parameters, provided behavioral improvement, and corrected the pathological phenotype in the brain, retina, and heart of Ndufs4 KO mice. These results provide a robust proof that gene therapy strategies targeting multiple organs can rescue fatal neurometabolic disorders with CNS involvement.

neuroscience↗

bioRxiv2019

α-synuclein in the retina leads to degeneration of dopamine amacrine cells impairing vision

Introduction-synuclein aggregates have been identified in the retina of Parkinsons disease patients associated to vision impairment. In this study, we sought to determine the effects of -synuclein overexpression on the survival and function of dopaminergic (DA) amacrine cells in the retina.\n\nMethodsAdult mice were intravitreally injected with an adeno-associated viral (AAV) vector to overexpress human wild-type -synuclein in the inner retina. Following systemic injections of levodopa (L-DOPA), retinal responses and visual acuity driven behavior were measured by electroretinography (ERG) and water maze task, respectively. Amacrine cells and ganglion cells were counted at 1, 2 and 3 months post-injection.\n\nResults-synuclein led to an early loss of DA cells, which was associated with the decrease of light-adapted ERG responses and visual acuity. Systemic injections of L-DOPA rescued these retinal and visual abnormalities.\n\nConclusionsThe data show that -synuclein affects dopamine neurons in the retina. The approach provides a novel accessible mode of modeling the underlying mechanisms implicated in synucleinophaties pathogenesis and for testing novel treatments.

neuroscience↗