Lysosomal and mTORC1 signaling dysregulation underpin the pathology of spastic paraplegia type 80.

Endosomal sorting complex required for transport (ESCRT) is the major membrane remodeling complex, closely associated with endolysosomal repair and hereditary spastic paraplegias (HSP) diseases. Loss of function mutations in the ESCRT-I component UBAP1 causes a rare type of HSP (spastic paraplegia 80, SPG80), while the underlying pathological mechanism is unclear. Here, we found that UBAP1 but not SPG80 causing mutant was efficiently recruited to damaged lysosomes and mediated lysosome recovery. Loss of UBAP1 results in dysfunction of lysosomes, disconnecting mTOR localization on lysosomes, leading to cytoplasmic mTORC1 activation and TFEB dephosphorylation, as confirmed in vitro and in vivo models. Administration of rapamycin, a specific inhibitor of mTORC1, enhances mTOR lysosomal localization and TFEB phosphorylation. This pharmacological intervention effectively attenuated disease progression and restored lysosomal homeostasis in Ubap1 deficiency mice. Our findings reveal UBAP1's role in lysosome regulation and suggest rapamycin may benefit patients with HSP and other motor neuron disorders.