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

Yiqiang Zhi, Tongtong Zhang, Danping Lu, Shuhuai Lin, Huizhen Su, Yupei Wu, Qiyuan Chang, Shuyuan Wang, Chenning Lv, Honggao Fu, Li-Yu Chen, Wan-Jin Chen, Ning Wang, Zhifei Fu (), Xiang Lin () and Dan Xu ()
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Yiqiang Zhi: Fujian Medical University
Tongtong Zhang: Fujian Medical University
Danping Lu: Fujian Agriculture and Forestry University
Shuhuai Lin: Fujian Medical University
Huizhen Su: Fujian Medical University
Yupei Wu: Fujian Medical University
Qiyuan Chang: Fujian Medical University
Shuyuan Wang: Fujian Medical University
Chenning Lv: Fujian Medical University
Honggao Fu: Fujian Medical University
Li-Yu Chen: Fujian Agriculture and Forestry University
Wan-Jin Chen: Fujian Medical University
Ning Wang: Fujian Medical University
Zhifei Fu: Fujian Medical University
Xiang Lin: Fujian Medical University
Dan Xu: Fujian Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-64800-5

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