Innovative high throughput screening identifies HSPB8 modulators counteracting misfolded protein accumulation in neurodegenerative diseases
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Data di Pubblicazione:
2023
Citazione:
Innovative high throughput screening identifies HSPB8 modulators counteracting misfolded protein accumulation in neurodegenerative diseases / M. Chierichetti, V. Crippa, P. Rusmini, V. Ferrari, B. Tedesco, E. Casarotto, M. Cozzi, P. Pramaggiore, L. Cornaggia, G. Patelli, M. Piccolella, M. Galbiati, R. Cristofani, A. Poletti. ((Intervento presentato al convegno National Meeting of PhD Students in Neuroscience tenutosi a Torino : 14 settembre nel 2023.
Abstract:
In different motoneuron diseases it has been demonstrated that overexpression of HSPB8, a key
component of the Chaperone-Assisted Selective Autophagy complex, enhance the degradation of
misfolded proteins causative of the disease. Therefore, for this type of diseases, could be
therapeutically relevant to pharmacologically enhance HSPB8 expression.
We designed a high throughput screening (HTS) able to identify compounds that either enhance
HSPB8 gene transcription and/or regulate HSPB8 translation and stability.
The HTS was performed using the compound collection of “Collezione nazionale di composti
Chimici e centro screening” (CNCCS) which contains available FDA- and/or EMA-approved drugs
and a range of chemotypes, from both commercial and non-commercial suppliers. A collection of
119,059 compounds was tested and, after a secondary dose/response screening, 14 compounds
were selected.
All compounds were confirmed to upregulate the endogenous HSPB8 mRNA and enhanced HSPB8
protein levels. Notably, 4 compounds interfered with the proteasomal degradative pathways,
which imply their exclusion as a potential compound of interest, due to the negative impact of
proteasome inhibition in those diseases. The formation of mutant SOD1 inclusions, causative of
some familial ALS forms, was prevented by 6 compounds and 3 of them were shown not to
interfere with the proteasome. Those 3 compounds named C, D and G showed different
mechanisms of action. Compounds C acted by stabilizing HSPB8 protein levels and mainly
prevented the maturation of mutant SOD1 aggregates to larger complexes, independently by
HSPB8 induction. While compounds D and G, mainly regulated HSPB8 mRNA levels and prevented
the formation of mutant SOD1 aggregates activating also crucial autophagic factors.
In conclusion further studies are needed to clarify which other factors may mediate these
differential effects of the three compounds, but they may represent valuable candidates to be
tested in pre-clinical studies aimed at counteracting proteotoxic activities in several types of
human disorders.
This research was funded by: CN3 - Centro Nazionale di Ricerca; “Collezione Nazionale dei
Composti Chimici e Centro di Screening” – CNCCS, Italy; Fondazione Telethon, Italy; Kennedy's
disease association; Fondazione Cariplo, Italy.
Tipologia IRIS:
14 - Intervento a convegno non pubblicato
Elenco autori:
M. Chierichetti, V. Crippa, P. Rusmini, V. Ferrari, B. Tedesco, E. Casarotto, M. Cozzi, P. Pramaggiore, L. Cornaggia, G. Patelli, M. Piccolella, M. Galbiati, R. Cristofani, A. Poletti
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