Complex interplay between the length and composition of the huntingtin-derived peptides modulates the intracellular behavior of the N-terminal fragments of mutant huntingtin
PBN-AR
Instytucja
Instytut Matki i Dziecka
Informacje podstawowe
Główny język publikacji
en
Czasopismo
European Journal of Cell Biology
ISSN
0171-9335
EISSN
Wydawca
ELSEVIER GMBH, URBAN & FISCHER VERLAG
DOI
URL
Rok publikacji
2015
Numer zeszytu
5
Strony od-do
179-189
Numer tomu
94
Identyfikator DOI
Liczba arkuszy
Słowa kluczowe
en
Huntington's disease
Huntingtin
Protein aggregation
Inclusion body
localization
Autophagy
Streszczenia
Język
en
Treść
Abstract Diverse subcellular localizations of the huntingtin-containing inclusion bodies are frequently suspected of reflecting crucial divisions between different cellular pathways contributing to the pathophysiology of Huntington's disease. Here, we use a panel of different N-terminal huntingtin fragments overexpressed in transfected neuronal and non-neuronal cells to demonstrate that it is the length of the N-terminal huntingtin fragments rather than a presence of any specific amino acid sequences that determines the ratio between the nuclear and cytoplasmic inclusion bodies. Importantly, the length of those fragments does also seem to strongly influence the folding of the aggregating huntingtin species, as indicated by the apparent differences in their accessibility for different antibodies directed against particular subdomains within the N-terminal part of huntingtin, although these differences do not correlate with the peptides’ ability to efficiently aggregate within the cell nucleus. Furthermore, the relatively long huntingtin fragment containing 588 amino acids of the reference sequence shows intracellular behavior that is substantially different from that exhibited by its shorter counterparts (containing either 171, 120, 89 or 64 amino acids), as this rarely aggregating peptide is not only accumulating in cytoplasmic inclusions of slightly different morphology but is also most strongly affected by the FLAG-tagging procedure that unexpectedly induces (or enhances) autophagy-related processes. Together, our results reveal a significant heterogeneity of the huntingtin accumulation patterns that are observed at the cellular level. These patterns are not only strongly dependent on both the length and the amino acid composition of the N-terminal huntingtin peptides but also seem to engage different cellular mechanisms implicated in the pathogenesis of Huntington's disease, including the non-proteasomal degradation of potentially toxic huntingtin forms.
Cechy publikacji
ORIGINAL_ARTICLE
Inne
System-identifier
592675
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