A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases

Cristofani, R.; Crippa, V.; Cicardi, M.E.; Tedesco, B.; Ferrari, V.; Chierichetti, M.; Casarotto, E.; Piccolella, Margherita; Messi, Elio; Galbiati, M.; Rusmini, P.; Poletti, Angelo

doi:10.3389/fnagi.2020.00191

Cited by 16 publications

(12 citation statements)

References 296 publications

(426 reference statements)

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“…Third, in patients with single-nucleotide polymorphisms that are not amenable to traditional gene replacement therapy because of potential dominant-negative effects, CRISPR/Cas9 may soon be used to correct functional single-nucleotide variants. And finally, while this Review has focused on the heart and cancer, we would be disingenuous if we did not report that an increasing number of studies suggest that targeting BAG3 may also be effective in the treatment of diseases attributable to abnormalities in PQC in the central nervous system, including Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease (133)(134)(135)…”

Section: Bag3 and The Heartmentioning

confidence: 98%

Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease

Kirk¹,

Cheung²,

Feldman³

2021

Journal of Clinical Investigation

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Conflict of interest: AMF is the founder of Renovacor Inc. and was a director of the company until it became public in 2021. His conflicts include ownership of equity, income, and research support. He is the inventor on US patent US20170016066A1 and European Union patent WO2019237002A1 (Optimization d'une thérapie génique de bag3). All patents have been licensed by Temple University to Renovacor Inc. JYC is an equity holder in Renovacor Inc.

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Section: Bag3 and The Heartmentioning

confidence: 98%

Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease

Kirk¹,

Cheung²,

Feldman³

2021

Journal of Clinical Investigation

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“…Therefore, BAG1 is not secreted, whereas BAG3 and HSPB8 are released in both types of EVs, suggesting that the HSP70 status is preferentially associated with its autophagic route. In fact, HSPB8 and BAG3, together with HSP70, are members of the CASA complex, which is responsible for misfolded proteins recognition and transport to autophagosomes for their disposal via autophagy [51][52][53]. In this context, the loading of the CASA complex-bound substrate into autophagosome is mediated by the SQSTM1/p62 autophagy receptor, but it requires the formation of a lipidated active form of MAP1LC3B (MAP1LC3B-II) that is anchored to the autophagosome membrane.…”

Section: Evs Contained Pqc System Components Involved In the Intracel...mentioning

confidence: 99%

Neurodegenerative Disease-Associated TDP-43 Fragments Are Extracellularly Secreted with CASA Complex Proteins

Casarotto

Sproviero²,

Gagliani

et al. 2022

Cells

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Extracellular vesicles (EVs) play a central role in neurodegenerative diseases (NDs) since they may either spread the pathology or contribute to the intracellular protein quality control (PQC) system for the cellular clearance of NDs-associated proteins. Here, we investigated the crosstalk between large (LVs) and small (SVs) EVs and PQC in the disposal of TDP-43 and its FTLD and ALS-associated C-terminal fragments (TDP-35 and TDP-25). By taking advantage of neuronal cells (NSC-34 cells), we demonstrated that both EVs types, but particularly LVs, contained TDP-43, TDP-35 and TDP-25. When the PQC system was inhibited, as it occurs in NDs, we found that TDP-35 and TDP-25 secretion via EVs increased. In line with this observation, we specifically detected TDP-35 in EVs derived from plasma of FTLD patients. Moreover, we demonstrated that both neuronal and plasma-derived EVs transported components of the chaperone-assisted selective autophagy (CASA) complex (HSP70, BAG3 and HSPB8). Neuronal EVs also contained the autophagy-related MAP1LC3B-II protein. Notably, we found that, under PQC inhibition, HSPB8, BAG3 and MAP1LC3B-II secretion paralleled that of TDP-43 species. Taken together, our data highlight the role of EVs, particularly of LVs, in the disposal of disease-associated TDP-43 species, and suggest a possible new role for the CASA complex in NDs.

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“…Inherited ALS cases are associated to both loss-of-function (LOF) and aberrant gain-of-function (GOF) mutations, as well as to mixed LOF and GOF, that can be found in more than 40 genes. Nonetheless, around 30% of fALS genetic causes still need to be identified, indicating that ALS is a disease with a widely heterogeneous genetic background (Cristofani et al 2020 ). Noteworthily, the wild-type forms of the gene products causing fALS display an aberrant behavior in sALS too, suggesting that the two forms of the disease probably share some pathogenetic mechanisms (Neumann et al 2006 ).…”

Section: Introductionmentioning

confidence: 99%

“…Autophagy includes three distinct pathways that promote and regulate the degradation of substrates via lysosomes, microautophagy (Schuck 2020 ), chaperone-mediated autophagy (CMA) (Kaushik and Cuervo 2018 ), and macroautophagy, that includes the chaperone assisted–selective autophagy or CASA (Cristofani et al 2020 ). Here we will focus on macroautophagy (hereafter autophagy).…”

Section: Introductionmentioning

confidence: 99%

Autophagy Dysfunction in ALS: from Transport to Protein Degradation

Cozzi

Ferrari

2022

J Mol Neurosci

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons (MNs). Since the identification of the first ALS mutation in 1993, more than 40 genes have been associated with the disorder. The most frequent genetic causes of ALS are represented by mutated genes whose products challenge proteostasis, becoming unable to properly fold and consequently aggregating into inclusions that impose proteotoxic stress on affected cells. In this context, increasing evidence supports the central role played by autophagy dysfunctions in the pathogenesis of ALS. Indeed, in early stages of disease, high levels of proteins involved in autophagy are present in ALS MNs; but at the same time, with neurodegeneration progression, autophagy-mediated degradation decreases, often as a result of the accumulation of toxic protein aggregates in affected cells. Autophagy is a complex multistep pathway that has a central role in maintaining cellular homeostasis. Several proteins are involved in its tight regulation, and importantly a relevant fraction of ALS-related genes encodes products that directly take part in autophagy, further underlining the relevance of this key protein degradation system in disease onset and progression. In this review, we report the most relevant findings concerning ALS genes whose products are involved in the several steps of the autophagic pathway, from phagophore formation to autophagosome maturation and transport and finally to substrate degradation.

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A Crucial Role for the Protein Quality Control System in Motor Neuron Diseases

Cited by 16 publications

References 296 publications

Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease

Therapeutic targeting of BAG3: considering its complexity in cancer and heart disease

Neurodegenerative Disease-Associated TDP-43 Fragments Are Extracellularly Secreted with CASA Complex Proteins

Autophagy Dysfunction in ALS: from Transport to Protein Degradation

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