Absence of Rab39b-induced macroautophagy impairment increases neurotoxic α-synuclein and causes degeneration of substantia nigra dopaminergic neurons in mouse model of X-linked Parkinson's disease

Ching-Chi Chiu; Yi-Hsin Weng; Tu-Hsueh Yeh; Wan-Shia Chen; Shu-Yu Liu; Tai-Ju Chiu; Allen Hon-Lun Li; Hung-Li Wang

doi:10.1016/j.lfs.2025.123789

Absence of Rab39b-induced macroautophagy impairment increases neurotoxic α-synuclein and causes degeneration of substantia nigra dopaminergic neurons in mouse model of X-linked Parkinson's disease

Life Sci. 2025 Jun 3:377:123789. doi: 10.1016/j.lfs.2025.123789. Online ahead of print.

Authors

Ching-Chi Chiu¹, Yi-Hsin Weng², Tu-Hsueh Yeh³, Wan-Shia Chen⁴, Shu-Yu Liu⁴, Tai-Ju Chiu⁵, Allen Hon-Lun Li⁶, Hung-Li Wang⁷

Affiliations

¹ Department of Medical Biotechnology and Laboratory Science, Chang Gung University College of Medicine, Taoyuan, Taiwan; Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Healthy Aging Research Center, Chang Gung University College of Medicine, Taoyuan, Taiwan.
² Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.
³ Department of Neurology, Taipei Medical University Hospital, Taipei, Taiwan.
⁴ Department of Physiology and Pharmacology, Chang Gung University College of Medicine, Taoyuan, Taiwan.
⁵ Graduate Institute of Biomedical Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan.
⁶ Department of Anesthesiology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan.
⁷ Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Healthy Aging Research Center, Chang Gung University College of Medicine, Taoyuan, Taiwan; Division of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Department of Physiology and Pharmacology, Chang Gung University College of Medicine, Taoyuan, Taiwan. Electronic address: hlwns@mail.cgu.edu.tw.

PMID: 40473068
DOI: 10.1016/j.lfs.2025.123789

Abstract

Deletion or mutation of RAB39B gene causes RAB39B deficiency in male patients and resulting X-linked Parkinson's disease (PD). Male Rab39b knockout (Rab39b^-/Y) mouse, which simulates PD RAB39B genetic mutation-induced absence of functional RAB39B, was prepared to study pathomechanisms of RAB39B deficiency-evoked neurodegeneration of substantia nigra (SN) dopaminergic cells. Rab39b^-/Y mice manifested PD motor impairment, degeneration of SN dopaminergic neurons and presence of SN Lewy bodies. Rab39b insufficiency caused macroautophagy impairment via reducing Atg3, Atg5, Atg7, Atg12 and Atg16L1 in SN. Rab39b deficiency-induced macroautophagy impairment upregulated α-synuclein within SN dopaminergic neurons and α-synuclein oligomers in SN. Macroautophagy activator rapamycin reversed macroautophagy dysfunction or upregulation of SN α-synuclein and ameliorated motor deficits and demise of SN dopaminergic neurons in Rab39b^-/Y mice. Rab39b paucity-promoted upregulation of ER α-synuclein activated ER stress-triggered apoptotic signaling in SN. Rab39b insufficiency increased SN mitochondrial α-synuclein and produced mitochondrial defect and oxidative stress. Rab39b deficiency-induced ER stress apoptotic signaling, mitochondrial impairment and oxidative damage activated mitochondrial pro-apoptotic pathway in SN. Rab39b deficiency-induced upregulation of α-synuclein oligomers induced excitation of SN microglia and NLRP3 inflammasome and elevation of IL-1β, IL-18 or TNF-α. Rab39b paucity-induced upregulation of pro-inflammatory cytokines activated MKK4-JNK -c-Jun/ATF-2 pro-apoptotic cascade and RIPK1-RIPK3-MLKL necroptotic pathway in SN. Our results suggest that RAB39B deficiency causes demise of SN dopaminergic neurons and X-linked PD by impairing macroautophagy and upregulating neurotoxic α-synuclein, which stimulates ER stress and mitochondrial apoptotic cascades and activates microglia and NLRP3 inflammasome. Our data also suggest that rapamycin possesses therapeutic effects on RAB39B mutation-induced X-linked PD.

Keywords: ER stress pro-apoptotic signaling; Macroautophagy impairment; Microglia; Mitochondrial apoptotic cascade; RAB39B; X-linked Parkinson's disease; α-Synuclein.