Mucopolysaccharidosis IIIA is a neuronopathic lysosomal storage disease, characterised by heparan sulphate and other substrates accumulating in the brain. Patients develop behavioural disturbances and cognitive decline, a possible consequence of neuroinflammation and abnormal substrate accumulation. Interleukin (IL)‐1β and interleukin‐1 receptor antagonist (IL‐1Ra) expression were significantly increased in both murine models and human MPSIII patients. We identified pathogenic mechanisms of inflammasome activation, including that disease‐specific 2‐O‐sulphated heparan sulphate was essential for priming an IL‐1β response via the Toll‐like receptor 4 complex. However, mucopolysaccharidosis IIIA primary and secondary storage substrates, such as amyloid beta, were both required to activate the NLRP3 inflammasome and initiate IL‐1β secretion. IL‐1 blockade in mucopolysaccharidosis IIIA mice using IL‐1 receptor type 1 knockout or haematopoietic stem cell gene therapy over‐expressing IL‐1Ra reduced gliosis and completely prevented behavioural phenotypes. In conclusion, we demonstrate that IL‐1 drives neuroinflammation, behavioural abnormality and cognitive decline in mucopolysaccharidosis IIIA, highlighting haematopoietic stem cell gene therapy treatment with IL‐1Ra as a potential neuronopathic lysosomal disease treatment.

Mitochondrial biogenesis requires the import of most of their proteins from the cytosol. Therefore, efficient import apparatus is vital for eukaryotic cell function, particularly in highly energy demanding cells such as neurons and myocytes. Consequently, dysfunctional mitochondrial protein import is implicated in many diseases. This study explores the molecular basis and consequences of import failure in mammalian cells. We show that blocking import machinery has profound effects on mitochondrial ultra-structure and dynamics, but surprisingly little impact on import. The explanation is a remarkable mechanism in which healthy cells transfer mitochondria to cells with deficient mitochondrial import, and vice versa, through connecting tunnelling nanotubes. These observations suggest the existence of a widespread mechanism for rescue of mitochondrial import function in complex multicellular organisms.