Biology subjects

Persichetti, F.

Publications and source records attributed to Persichetti, F..

3 recordsLinked to original sources

bioRxiv2023

Internal Ribosome Entry Sites act as Effector Domain in linear and circular antisense long non-coding SINEUP RNAs

SINEUPs are antisense long non-coding RNAs that enhance translation of overlapping sense mRNAs through the activity of two domains: a SINEB2 sequence UP-regulating translation (Effector Domain, ED) and an antisense region providing target specificity (Binding Domain, BD). In this study, we demonstrate that the invSINEB2 sequence from the natural SINEUP AS Uchl1 RNA is an Internal Ribosomal Entry Site (IRES) when acting in cis and that known viral and cellular IRES sequences can act as Effector Domain in synthetic SINEUPs. To identify natural IRES-containing, non-coding RNAs with SINEUP-like activity, we focused on circular RNAs showing that the non-coding circ5533, transcribed from the c-myc locus, enhances endogenous protein expression of its target PX Domain Containing Serine/Threonine Kinase Like (Pxk) by increasing mRNA association to polysomes. In summary, this study shows that natural and synthetic SINEUPs include linear and circular transcripts with an embedded IRES sequence as ED.

molecular biology↗

bioRxiv2021

Neuronal hemoglobin induces α-synuclein cleavage and loss of dopaminergic neurons

BackgroudParkinsons disease (PD) presents the selective loss of A9 dopaminergic (DA) neurons of Substantia Nigra pars compacta (SNpc) and the presence of intracellular aggregates called Lewy bodies. -synuclein (-syn) species truncated at the carboxy terminal (C-terminal) accumulate in pathological inclusions and promote -syn aggregation and toxicity. Hemoglobin (Hb) is the major oxygen carrier protein in erythrocytes. In addition, Hb is expressed in A9 DA neurons where it influences mitochondrial activity. Hb overexpression increases cells vulnerability in a neurochemical model of PD in vitro and forms cytoplasmic and nucleolar aggregates upon short-term overexpression in mouse SNpc. Methods and {beta}-globin chains were co-expressed in DA cells of SNpc in vivo upon stereotaxic injections of an Adeno-Associated Virus isotype 9 (AAV9) and in DA iMN9D cells in vitro. ResultsLong-term Hb over-expression in SNpc induced the loss of about 50% of DA neurons, a mild motor impairment and deficits in recognition and spatial working memory. Hb triggered the formation of endogenous -synuclein C-terminal truncated species. Similar -syn fragments were found in vitro in DA iMN9D cells over-expressing and {beta}-globins when treated with pre-formed -syn fibrils. ConclusionOur study positions Hb as a relevant player in PD pathogenesis for its ability to trigger DA cells loss in vivo and the formation of C-terminal -synuclein fragments.

neuroscience↗

bioRxiv2020

Transposable Element activation promotes neurodegeneration in a Drosophila model of Huntington's disease

Huntingtons disease (HD) is a late-onset, autosomal dominant disorder characterized by progressive motor dysfunction, cognitive decline and psychiatric disturbances. The most prominent pathological manifestation is a selective loss of medium-sized spiny neurons of the striatum. The disease is caused by a CAG repeat expansion in the IT15 gene, which elongates a stretch of polyglutamine at the amino-terminal of the HD protein, Huntingtin (Htt). Despite the accumulation of an impressive amount of data on the molecular basis of neurodegeneration, no therapeutic treatments are available and new pharmacological targets are needed. Transposable Elements (TEs) are mobile genetic elements that constitute a large fraction of eukaryotic genomes. Retrotransposons (RTEs) replicate through an RNA intermediate and represent approximately 40% and 30% of the human and Drosophila genomes. Mounting evidence suggests that mammalian RTEs are normally active during neurogenesis and may be involved in diseases of the nervous system. Here we show that TE expression and mobilization are increased in a Drosophila melanogaster HD model. By inhibiting TE mobilization with Reverse Transcriptase inhibitors, polyQ-dependent eye neurodegeneration and genome instability in larval brains are rescued and fly lifespan is increased. These results suggest that TE activation may be involved in polyQ-induced neurotoxicity and a potential pharmacological target.

neuroscience↗