Höfundar:
Morteza Bajgiran, Rannveig Kristjánsdóttir, Zophonías Oddur Jónsson, Sigríður Rut Franzdóttir
Neuronal dysfunction can arise from the build up of aggregated, intrinsically-disordered or misfolded proteins that cannot be properly degraded. The degradation capacity of neurons is determined by the ubiquitin-proteasome system (UPS) and autophagy. When this capacity is exceeded, aggregates form an aggresome, which promotes autophagic clearance of aggregates by arranging misfolded proteins into a single location. This process is facilitated by proteasome components, chaperones, and other proteins such as HDAC6 and P62. Depletion of the conserved ATPases, Pontin and Reptin, impairs the formation of the aggresome in cultured cells. In Drosophila melanogaster, aggregate-like swellings in neurons and neurological dysfunction were observed upon loss of Pontin and Reptin. This study investigates the potential roles of the proteins in the clearance of aggregates and maintenance of proteostasis in the nervous system of Drosophila melanogaster.
Genetic tools were used to specifically knock down pontin and reptin expression in motor neurons, followed by immunostaining for poly-ubiquitinated proteins and components of the autophagic machinery.
We find that decreased expression of the proteins causes accumulation of poly-ubiquitinated proteins, and these become widespread along axons, with apparently disrupted transport to the soma and lack of aggresome formation. Similarly, p62 distribution is affected, and we are currently inverstigating potential interplay with the autophagic machinery at sites of aggregation and in the soma.
In conclusion, Pontin and Reptin are required to maintain healthy neurons, and, in addition to their numerous other cellular roles, seem to be an essential part of the proteostatic machinery.