Titolo progetto: Identification and targeting of dsRNA of endogenous retroviral origin in Amyotrophic lateral sclerosis motoneurons.

Programma di finanziamento: RNA & Gene therapy: Bando pubblico per la selezione di proposte progettuali da finanziare nell'ambito dell'attività di ricerca dello spoke n. 3 "Neurodegeneration" Track A1. Identificazione e validazione di molecole di RNA terapeutiche per malattie del sistema nervoso.

Responsabile scientifico: prof. Eros Di Giorgio

Ruolo del DMED: coordinatore

Descrizione generale:

Amyotrophic lateral sclerosis (ALS) is characterized by progressive death of motor neurons. Uncontrolled and progressive TDP-43 proteinopathy has been correlated to the progression of most sporadic and certain familiar ALS. Accordingly to this “prion-like” model, the aggregation of TDP-43 proteins in the first motoneuron organizes the aggregation of other TDP-43 centers in adjacent cells leading to neurodegenerative propagation through neuronal tissue. However, ALS is not infective and injection of aggregated TDP-43 does not trigger ALS. Increased reverse transcriptase activity was measured in the serum from ALS patients and increased ERVK transcript levels were found in post-mortem ALS brain. On the basis of these two pieces of evidence, researchers in the field hypothesized that the derepression of endogenous retroviruses (ERVs) could underlie the aggregation of TDP-43 and the pathogenesis of ALS. Jagged and debated evidence has been brought to support the active role played by the depression of actively transposing ERVs of the K family in infecting adjacent motor neurons and favoring the progression of the disease. We have recently demonstrated that the failure of functioning epigenetic surveillance mechanisms leads in senescence cells to the de-repression of ERVs that folds as immunogenic dsRNAs which, through the activation of the MDA5/MAVS pathway, determine the release of cytokines and inflammatory mediators that determine the so-called lateral senescence in adjacent cells as well as the induction of proteotoxic stress and an increased basal level of apoptosis. We believe that a similar uncontrolled accumulation of dsRNA of ERV origin underlies the pathogenesis of ALS and we therefore aim to: a) identify the dysregulated dsRNA ERV species by RNA-seq and dsRNA-seq in motor neurons derived from iPSCs obtained from ALS patients; b) adopt a Cas13-ADAR2 system to achieve destabilization of the identified dysregulated ERV species; c) restore optimal motoneuronal fitness. The project aims to: WP1) identify the dysregulated dsRNA Endogenous retroviral (ERV) species by RNA-seq and dsRNA-seq in motor neurons derived from iPSCs obtained from ALS patients; WP2) adopt a Cas13-ADAR2 system to achieve destabilization of the identified dysregulated ERV species and: WP3) evaluate the impact oftheir repression in restoring optimal motoneuronal fitness and decreasing TDP-43 proteinopathy.

Partner del progetto:

• Università degli studi di Udine

Date inizio e fine progetto: 11.09.2024 – 10.09.2025

Budget totale del progetto: 72.000 €

Iniziativa finanziata dall’Unione europea –NextGenerationEU.