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.

Deletion or mutation of RAB39B gene causes RAB39B deficiency in male patients and resulting X-linked Parkinson's disease (PD). Male Rab39b knockout (Rab39b) 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 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 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.