: Conformational diseases, such as Alzheimer, Parkinson and Huntington diseases, are part of a common class of neurological disorders characterized by the aggregation and progressive accumulation of proteins bearing aberrant conformations. Huntington disease (HD) has autosomal dominant inheritance and is caused by mutations leading to an abnormal expansion in the polyglutamine (polyQ) tract of the huntingtin (HTT) protein, leading to the formation of HTT inclusion bodies in neurons of affected patients. Interestingly, recent experimental evidence is challenging the conventional view by which the disease pathogenesis is solely a consequence of the intracellular accumulation of mutant protein aggregates. These studies reveal that transcellular transfer of mutated huntingtin protein is able to seed oligomers involving even the wild type forms of the protein. To date, there is still no successful strategy to treat HD. Here we describe a novel functional role for the HSPB1-p62/SQSTM1 complex, which acts as a cargo loading platform, allowing the unconventional secretion of mutant HTT by extracellular vesicles (EVs). HSPB1 interacts preferentially with polyQ-expanded HTT compared with the wild type protein and affects its aggregation. Furthermore, HSPB1 levels correlate with the rate of mutant HTT secretion, which is controlled by the activity of the PI3K/AKT/mTOR signalling pathway. Finally, we show that these HTT-containing vesicular structures are biologically active and able to be internalised by recipient cells, therefore providing an additional mechanism to explain the prion-like spreading properties of mutant HTT. These findings have implications for turn-over of disease-associated, aggregation-prone proteins.

The HSPB1-p62/SQSTM1 functional complex regulates the unconventional secretion and transcellular spreading of the HD-associated mutant huntingtin protein / Bonavita, Raffaella; Scerra, Gianluca; Di Martino, Rosaria; Nuzzo, Silvia; Polishchuk, Elena; Di Gennaro, Mariagrazia; Williams, Sarah V; Caporaso, Maria Gabriella; Caiazza, Carmen; Polishchuk, Roman; D'Agostino, Massimo; Fleming, Angeleen; Renna, Maurizio. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - 32:14(2023), pp. 2269-2291. [10.1093/hmg/ddad047]

The HSPB1-p62/SQSTM1 functional complex regulates the unconventional secretion and transcellular spreading of the HD-associated mutant huntingtin protein

Bonavita, Raffaella;Scerra, Gianluca;Di Martino, Rosaria;Nuzzo, Silvia;Di Gennaro, Mariagrazia;Caporaso, Maria Gabriella;Caiazza, Carmen;Polishchuk, Roman;Fleming, Angeleen;Renna, Maurizio
2023

Abstract

: Conformational diseases, such as Alzheimer, Parkinson and Huntington diseases, are part of a common class of neurological disorders characterized by the aggregation and progressive accumulation of proteins bearing aberrant conformations. Huntington disease (HD) has autosomal dominant inheritance and is caused by mutations leading to an abnormal expansion in the polyglutamine (polyQ) tract of the huntingtin (HTT) protein, leading to the formation of HTT inclusion bodies in neurons of affected patients. Interestingly, recent experimental evidence is challenging the conventional view by which the disease pathogenesis is solely a consequence of the intracellular accumulation of mutant protein aggregates. These studies reveal that transcellular transfer of mutated huntingtin protein is able to seed oligomers involving even the wild type forms of the protein. To date, there is still no successful strategy to treat HD. Here we describe a novel functional role for the HSPB1-p62/SQSTM1 complex, which acts as a cargo loading platform, allowing the unconventional secretion of mutant HTT by extracellular vesicles (EVs). HSPB1 interacts preferentially with polyQ-expanded HTT compared with the wild type protein and affects its aggregation. Furthermore, HSPB1 levels correlate with the rate of mutant HTT secretion, which is controlled by the activity of the PI3K/AKT/mTOR signalling pathway. Finally, we show that these HTT-containing vesicular structures are biologically active and able to be internalised by recipient cells, therefore providing an additional mechanism to explain the prion-like spreading properties of mutant HTT. These findings have implications for turn-over of disease-associated, aggregation-prone proteins.
2023
The HSPB1-p62/SQSTM1 functional complex regulates the unconventional secretion and transcellular spreading of the HD-associated mutant huntingtin protein / Bonavita, Raffaella; Scerra, Gianluca; Di Martino, Rosaria; Nuzzo, Silvia; Polishchuk, Elena; Di Gennaro, Mariagrazia; Williams, Sarah V; Caporaso, Maria Gabriella; Caiazza, Carmen; Polishchuk, Roman; D'Agostino, Massimo; Fleming, Angeleen; Renna, Maurizio. - In: HUMAN MOLECULAR GENETICS. - ISSN 0964-6906. - 32:14(2023), pp. 2269-2291. [10.1093/hmg/ddad047]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/919906
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