In order to be biologically active, every nascent polypeptide emerging from the ribosomes should fold and acquire its native conformation. Non-native conformations lead to drastic events ranging from compromised biological activity of the protein to its tendency to (self)aggregate or inappropriately interact with cellular components. Heat Shock Proteins (HSP) act as molecular chaperones and form the first line of defense in chaperoning protein folding. It is known that with aging, there is a decline in the functionality of chaperone networks and also, accumulation of damaged proteins occurs. Together this has a cumulative effect on protein-homeostasis and leads to protein-aggregation-late-onset neurodegenerative diseases like Huntington’s disease (HD). The work in this thesis identified DNAJB6 as the most potent suppressor of HD phenotype and it not only improves quality but quantity of life in HD mouse model. So far it’s the largest effect for a single HSP reported for HD mouse model and thus identifies DNAJB6 as a promising target in CAG repeat diseases. Also, it is clear that different aggregation-prone proteins require different HSP handling. While some require enhanced assistance for folding, others may never reach the proper folded state and hence needs to be degraded. Thus, an important distinction may have to be made for chaperones that relieve the consequences of aggregates in a specific disease (symptomatic relief) and chaperones that delay the initiation of the disease process (delay protein aggregation). So, depending on the relative contribution of different folding and aggregation problems, different chaperones may be required to combat neurodegeneration.
|Translated title of the contribution||DNAJ eiwitten: meer dan alleen "co-chaperonnes": Implicaties voor eiwit-aggregatie ziektes|
|Place of Publication||[S.l.]|
|Publication status||Published - 2014|