Titolo: Role of amyloid aggregation and autophagy dysfunction in neuroinflammatory astrocytes of neuronopathic MPS

Codice Progetto: P2022SB2CS

Responsabile scientifico: Prof. Enrico Moro
Coordinatore: Università degli Studi di NAPOLI Federico II - Prof. Alessandro Fraldi

Partner-Unità di ricerca: Università degli Studi di PADOVA

Bando: PRIN 2022 PRIN - Decreto Direttoriale n. 1409 del 14-09-2022
Durata: 30/11/2023 - 29/11/2025 (24 mesi)

Finanziamento progetto: € 224.700,00

 

Abstract del progetto

Neuronopathic Mucopolysaccharidoses (nMPSs) are inherited lysosomal disorders, characterized by severe neurological and behavioral abnormalities, progressive neuroinflammation and neurodegeneration. Despite the development of promising life-saving therapeutic approaches, neurological symptoms are still incurable and most-patients suffer from life-threatening conditions, which often represent a huge economic and social burden to the society. To design a breakthrough therapy for the nMPS-related neurological manifestations, the whole spectrum of cellular defects triggered by lysosomal dysfunction should be taken into account. These abnormalities range from impaired autophagy and proteostasis with increased oxidative stress, to altered cell signaling transduction, which altogether lead to progressive neuronal cell loss and neuroinflammation. In particular, a defective autophagosomal-lysosomal pathway (ALP) is known to lead to proteostasis disruption and protein aggregation, which are crucial drivers of neurodegeneration. Additionally, aggregation of amyloid proteins itself may affect ALP, thus generating a vicious cycle and boosting neurodegeneration. While these processes in the brain have been mostly studied in neurons, their contribution in astrocytes to neurodegeneration represents an underexplored field. Using experimental models for MPS-II and MPS-IIIA, we will investigate whether amyloid aggregation and ALP dysfunction contribute to the loss of cellular homeostasis and proinflammatory changes in reactive astrocytes. We will next assess whether and how these detrimental astrocyte-related events may contribute to the neuronal demise. Our results may shed light on neglected aspects of the nMPS-related neurodegeneration, thus paving the way for the development of alternative therapeutic approaches.