The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell Death
Misfolding protein diseases are a wide class of disorders in which the aberrantly folded protein aggregates accumulate in affected cells. In the brain and in the skeletal muscle, misfolded protein accumulation induces a variety of cell dysfunctions that frequently lead to cell death. In motoneuron d...
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Frontiers Media S.A.
2019-08-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2019.00796/full |
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| author | Riccardo Cristofani Paola Rusmini Mariarita Galbiati Maria Elena Cicardi Veronica Ferrari Barbara Tedesco Elena Casarotto Marta Chierichetti Elio Messi Margherita Piccolella Serena Carra Valeria Crippa Angelo Poletti Angelo Poletti |
| author_facet | Riccardo Cristofani Paola Rusmini Mariarita Galbiati Maria Elena Cicardi Veronica Ferrari Barbara Tedesco Elena Casarotto Marta Chierichetti Elio Messi Margherita Piccolella Serena Carra Valeria Crippa Angelo Poletti Angelo Poletti |
| author_sort | Riccardo Cristofani |
| collection | DOAJ |
| description | Misfolding protein diseases are a wide class of disorders in which the aberrantly folded protein aggregates accumulate in affected cells. In the brain and in the skeletal muscle, misfolded protein accumulation induces a variety of cell dysfunctions that frequently lead to cell death. In motoneuron diseases (MNDs), misfolded proteins accumulate primarily in motoneurons, glial cells and/or skeletal muscle cells, altering motor function. The deleterious effects of misfolded proteins can be counteracted by the activity of the protein quality control (PQC) system, composed of chaperone proteins and degradative systems. Here, we focus on a PQC system component: heat shock protein family B (small) member 8 (HSPB8), a chaperone induced by harmful stressful events, including proteotoxicity. In motoneuron and muscle cells, misfolded proteins activate HSPB8 transcription and enhance HSPB8 levels, which contributes to prevent aggregate formation and their harmful effects. HSPB8 acts not only as a chaperone, but also facilitates the autophagy process, to enable the efficient clearance of the misfolded proteins. HSPB8 acts as a dimer bound to the HSP70 co-chaperone BAG3, a scaffold protein that is also capable of binding to HSP70 (associated with the E3-ligase CHIP) and dynein. When this complex is formed, it is transported by dynein to the microtubule organization center (MTOC), where aggresomes are formed. Here, misfolded proteins are engulfed into nascent autophagosomes to be degraded via the chaperone-assisted selective autophagy (CASA). When CASA is insufficient or impaired, HSP70 and CHIP associate with an alternative co-chaperone, BAG1, which routes misfolded proteins to the proteasome for degradation. The finely tuned equilibrium between proteasome and CASA activity is thought to be crucial for maintaining the functional cell homeostasis during proteotoxic stresses, which in turn is essential for cell survival. This fine equilibrium seems to be altered in MNDs, like Amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), contributing to the onset and the progression of disease. Here, we will review how misfolded proteins may affect the PQC system and how the proper activity of this system can be restored by boosting or regulating HSPB8 activity, with the aim to ameliorate disease progression in these two fatal MNDs. |
| first_indexed | 2024-12-13T02:41:56Z |
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| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-13T02:41:56Z |
| publishDate | 2019-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neuroscience |
| spelling | doaj.art-8486cf4eec324891a476847490c152772022-12-22T00:02:17ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2019-08-011310.3389/fnins.2019.00796466993The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell DeathRiccardo Cristofani0Paola Rusmini1Mariarita Galbiati2Maria Elena Cicardi3Veronica Ferrari4Barbara Tedesco5Elena Casarotto6Marta Chierichetti7Elio Messi8Margherita Piccolella9Serena Carra10Valeria Crippa11Angelo Poletti12Angelo Poletti13Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza Sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza Sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza Sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza Sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza Sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza Sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza Sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza Sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza Sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza Sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, ItalyDipartimento di Scienze Biomediche, Metaboliche e Neuroscienze, Università di Modena e Reggio Emilia, Modena, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza Sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, ItalyDipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Centro di Eccellenza Sulle Malattie Neurodegenerative, Università degli Studi di Milano, Milan, ItalyCentro Interuniversitario Sulle Malattie Neurodegenerative, Università degli Studi di Firenze, Roma Tor Vergata, Milan, ItalyMisfolding protein diseases are a wide class of disorders in which the aberrantly folded protein aggregates accumulate in affected cells. In the brain and in the skeletal muscle, misfolded protein accumulation induces a variety of cell dysfunctions that frequently lead to cell death. In motoneuron diseases (MNDs), misfolded proteins accumulate primarily in motoneurons, glial cells and/or skeletal muscle cells, altering motor function. The deleterious effects of misfolded proteins can be counteracted by the activity of the protein quality control (PQC) system, composed of chaperone proteins and degradative systems. Here, we focus on a PQC system component: heat shock protein family B (small) member 8 (HSPB8), a chaperone induced by harmful stressful events, including proteotoxicity. In motoneuron and muscle cells, misfolded proteins activate HSPB8 transcription and enhance HSPB8 levels, which contributes to prevent aggregate formation and their harmful effects. HSPB8 acts not only as a chaperone, but also facilitates the autophagy process, to enable the efficient clearance of the misfolded proteins. HSPB8 acts as a dimer bound to the HSP70 co-chaperone BAG3, a scaffold protein that is also capable of binding to HSP70 (associated with the E3-ligase CHIP) and dynein. When this complex is formed, it is transported by dynein to the microtubule organization center (MTOC), where aggresomes are formed. Here, misfolded proteins are engulfed into nascent autophagosomes to be degraded via the chaperone-assisted selective autophagy (CASA). When CASA is insufficient or impaired, HSP70 and CHIP associate with an alternative co-chaperone, BAG1, which routes misfolded proteins to the proteasome for degradation. The finely tuned equilibrium between proteasome and CASA activity is thought to be crucial for maintaining the functional cell homeostasis during proteotoxic stresses, which in turn is essential for cell survival. This fine equilibrium seems to be altered in MNDs, like Amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), contributing to the onset and the progression of disease. Here, we will review how misfolded proteins may affect the PQC system and how the proper activity of this system can be restored by boosting or regulating HSPB8 activity, with the aim to ameliorate disease progression in these two fatal MNDs.https://www.frontiersin.org/article/10.3389/fnins.2019.00796/fullmotoneuron diseasesamyotrophic lateral sclerosisspinal and bulbar muscular atrophyproteasomeautophagychaperones |
| spellingShingle | Riccardo Cristofani Paola Rusmini Mariarita Galbiati Maria Elena Cicardi Veronica Ferrari Barbara Tedesco Elena Casarotto Marta Chierichetti Elio Messi Margherita Piccolella Serena Carra Valeria Crippa Angelo Poletti Angelo Poletti The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell Death Frontiers in Neuroscience motoneuron diseases amyotrophic lateral sclerosis spinal and bulbar muscular atrophy proteasome autophagy chaperones |
| title | The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell Death |
| title_full | The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell Death |
| title_fullStr | The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell Death |
| title_full_unstemmed | The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell Death |
| title_short | The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell Death |
| title_sort | regulation of the small heat shock protein b8 in misfolding protein diseases causing motoneuronal and muscle cell death |
| topic | motoneuron diseases amyotrophic lateral sclerosis spinal and bulbar muscular atrophy proteasome autophagy chaperones |
| url | https://www.frontiersin.org/article/10.3389/fnins.2019.00796/full |
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