Adaptor protein complex 5-related hereditary spastic paraplegias

Hereditary spastic paraplegia (HSP) denotes a group of heterogeneous neurodegenerative disorders caused by the degeneration of upper motor neurons. More than 80 associated genes (SPG) have been described so far. SPG11 and SPG15 together are among the most common forms of autosomal-recessive HSP. Clinically, SPG11 and SPG15 cannot be distinguished. Hence, it was proposed that both proteins are pathogenetically linked. Moreover, SPG11 and SPG15 are closely related with SPG48, another form of autosomal-recessive HSP. SPG48 patients show mutations in the zeta subunit of the newly described adaptor protein complex-5 (AP-5). Clinically, these patients present a similar but milder phenotype compared with SPG11 and SPG15. In this study, we used Spg11, Zfyve26 and Spg48 Knockout (KO) mice to evaluate the role of SPG11, ZFYVE26 and AP-5 in the pathogenesis of HSP. We found structural alterations of the transGolgi network (TGN), an impairment of the retrieval of proteins from late endosomes to the TGN as well as an impairment of autophagic lysosome reformation (ALR) and autophagy. Moreover, we were able to show that PI4K2A accumulates in autofluorescent intraneuronal deposits of Spg11 KO and Zfyve26 KO mice. PI4K2A, one of the four kinases responsible for the production of phosphatidylinositol-4 phosphate (PdtIns(4)P) from PdtIns, was found to be increased in mouse embryonic fibroblasts (MEFs) and brain samples of both KO mice. Taken together, the results show that the loss of SPG11 and ZFYVE26 leads to an increased accumulation of PI4K2A in autofluorescent material. The accumulation of this kinase resulted in the increase of its product PdtIns(4)P. This may also lead to altered levels of PdtIns(4,5)P2 and thus to a dysregulated recruitment of the ALR effectors Clathrin and Dynamin 2. This in turn can result in impaired autophagy and neurodegeneration