Dystonin loss-of-function leads to impaired autophagosome-endolysosome pathway dynamics

摘要

The neuronal dystonin protein (DST-a) is a large cytoskeletal linker important for integrating the various components of the cytoskeleton. Recessive Dst mutations lead to a sensory neuropathy in mice, known as dystonia musculorum (Dst(dt)). The disease is characterized by ataxia, autonomic disturbances, and ultimately, death, which are associated with massive degeneration of the sensory neurons in the dorsal root ganglion (DRG). Recent investigation of Dst(dt) sensory neurons revealed an accumulation of autophagosomes and a disruption in autophagic flux, which was believed to be due to insufficient availability of motor protein. Motor protein levels and the endolysosomal pathway were assessed in pre-symptomatic (postnatal day 5; P5) and symptomatic (P15) stage wild-type and Dst(dt) DRGs. Levels of mRNA encoding molecular motors were reduced, although no significant reduction in the protein level was detected. An increase in lysosomal marker LAMP1 in medium-large size Dst(dt-27J) sensory neurons was observed, along with an accumulation of electron-light single-membraned vesicles in Dst(dt-27J) DRG tissue at the late stages of disease. These vesicles are likely to have been autolysosomes, and their presence in only late-stage Dst(dt-27J) sensory neurons is suggestive of a pathological defect in autophagy. Further investigation is necessary to confirm vesicle identity, and to determine the role of Dst-a in normal autophagic flux.