Abstract
Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease associated with protein misfolding and aggregation. Most cases are characterized by TDP-43 positive inclusions, while a minority of familial ALS cases are instead FUS and SOD1 positive respectively. Cells can generate inclusions of variable type including previously characterized aggresomes, IPOD or JUNQ structures depending on the misfolded protein. SOD1 invariably forms JUNQ inclusions but it remains unclear whether other ALS protein aggregates arise as one of these previously described inclusion types or form unique structures. Here we show that FUS variably partitioned to IPOD, JUNQ or alternate structures, contain a mobile fraction, were not microtubule dependent and initially did not contain ubiquitin. TDP-43 inclusions formed in a microtubule independent manner, did not contain a mobile fraction but variably colocalized to JUNQ inclusions and another alternate structure. We conclude that the RNA binding proteins TDP-43 and FUS do not consistently fit the currently characterised inclusion models suggesting that cells have a larger repertoire for generating inclusions than currently thought, and imply that toxicity in ALS does not stem from a particular aggregation process or aggregate structure.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is characterised by the progressive and selective death of upper and lower motor neurones in the motor cortex and spinal cord
An insoluble protein deposit (IPOD) compartment has been observed in yeast and mammalian cells and is a dense, immobile compartment consisting of insoluble protein aggregates that are not ubiquitinated[30,32]
While misfolded mutant SOD1 is consistently associated with JUNQ-like inclusions as reported previously[30,33], we report for the first time that while FUS and TDP-43 can form iPOD and/or JUNQ-like inclusions respectively they can partition to inclusions that are distinct from SOD1 inclusions, distinct from each other, and from other described inclusions types
Summary
Amyotrophic Lateral Sclerosis (ALS) is characterised by the progressive and selective death of upper and lower motor neurones in the motor cortex and spinal cord. While misfolded mutant SOD1 is consistently associated with JUNQ-like inclusions as reported previously[30,33], we report for the first time that while FUS and TDP-43 can form iPOD and/or JUNQ-like inclusions respectively they can partition to inclusions that are distinct from SOD1 inclusions, distinct from each other, and from other described inclusions types These data may suggest that cells have a broader array of pathways for generating proteinacious inclusions than originally thought, and imply that toxicity in ALS does not stem from a particular aggregation process or aggregate structure
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
