Expression of human Ras-related protein Rab39B variant T168K in Caenorhabditis elegans leads to motor dysfunction and dopaminergic neuron degeneration
Yixuan Zeng,
Tengteng Wu,
Fengyin Liang,
Simei Long,
Wenyuan Guo,
Yi Huang,
Zhong Pei
Affiliations
Yixuan Zeng
Department of Neurology, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People's Hospital, Shenzhen, China; Corresponding author.
Tengteng Wu
Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Fengyin Liang
Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Simei Long
Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Wenyuan Guo
Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Yi Huang
Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
Zhong Pei
Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Corresponding author.
Human RAB39B gene is related to familial early-onset Parkinson disease. In early adulthood, men with the RAB39B c.503C > A (Thr168Lys, p. T168K) mutation develop typical tremor, bradykinesia, and alpha-synuclein accumulation. We investigated the pathological mechanism of RAB39B T168K in a Caenorhabditis elegans model. In early adult C. elegans, RAB39B T168K led to dopaminergic neuron degeneration that presented as disrupted dendrites and blunt neuronal cells. Abnormal dopamine secretion was inferred from a decline in motor function and a positive basal slowing phenotype. Dopamine-associated tests confirmed that synthesis and recycling of dopamine were normal. The RAB39B T168K mutation might impair dopamine vesicular transmission from the presynaptic membrane to the synaptic gap in dopaminergic neurons. The release-dependent feedback mechanism in neurotransmitters regulates the balance of receptor activities. Protein-protein interactions network analysis revealed that RAB39B may also function in lysosomal degradation and autophagy. Impaired disposal of misfolded α-synuclein eventually leads to protein aggregation. Thus, like other members of the Rab family, RAB39B may be involved in vesicular transport associated with dopamine secretion and α-synuclein clearance.
