Recent genetic and biochemical evidence has improved our understanding of the pathomechanisms that lead to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative diseases with overlapping symptoms and causes. Impaired RNA metabolism, enhanced aggregation of protein-RNA complexes, aberrant formation of ribonucleoprotein (RNP) granules and dysfunctional protein clearance via autophagy are emerging as crucial events in ALS/FTD pathogenesis. Importantly, these processes interact at the molecular level, converging on a common pathogenic cascade. In this review, we summarize key principles underlying ALS and FTD, and we discuss how mutations in genes involved in RNA metabolism, protein quality control and protein degradation meet mechanistically to impair the functionality and dynamics of RNP granules, and how this leads to cellular toxicity and death. Finally, we describe recent advances in understanding signaling pathways that become dysfunctional in ALS/FTD, partly due to altered RNP granule dynamics, but also with stress granule-independent mechanisms and, thus could be promising targets for future therapeutic intervention.

ALS and FTD: Where RNA metabolism meets protein quality control / Mandrioli, J.; Mediani, L.; Alberti, S.; Carra, S.. - In: SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY. - ISSN 1084-9521. - 99:(2020), pp. 183-192. [10.1016/j.semcdb.2019.06.003]

ALS and FTD: Where RNA metabolism meets protein quality control

Mandrioli J.;Mediani L.;Carra S.
2020

Abstract

Recent genetic and biochemical evidence has improved our understanding of the pathomechanisms that lead to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative diseases with overlapping symptoms and causes. Impaired RNA metabolism, enhanced aggregation of protein-RNA complexes, aberrant formation of ribonucleoprotein (RNP) granules and dysfunctional protein clearance via autophagy are emerging as crucial events in ALS/FTD pathogenesis. Importantly, these processes interact at the molecular level, converging on a common pathogenic cascade. In this review, we summarize key principles underlying ALS and FTD, and we discuss how mutations in genes involved in RNA metabolism, protein quality control and protein degradation meet mechanistically to impair the functionality and dynamics of RNP granules, and how this leads to cellular toxicity and death. Finally, we describe recent advances in understanding signaling pathways that become dysfunctional in ALS/FTD, partly due to altered RNP granule dynamics, but also with stress granule-independent mechanisms and, thus could be promising targets for future therapeutic intervention.
1-lug-2019
99
183
192
ALS and FTD: Where RNA metabolism meets protein quality control / Mandrioli, J.; Mediani, L.; Alberti, S.; Carra, S.. - In: SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY. - ISSN 1084-9521. - 99:(2020), pp. 183-192. [10.1016/j.semcdb.2019.06.003]
Mandrioli, J.; Mediani, L.; Alberti, S.; Carra, S.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1221870
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