Clinical and Neuropathological Features Associated With Loss of RAB39B
Yujing Gao1,2, Verónica Martínez-Cerdeño3,4, Kirk J Hogan5,6
1Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
Background:
Pathogenic variants in the small GTPase Ras Analogue in Brain 39b (RAB39B) have been linked to the development of early-onset parkinsonism. The study was aimed at delineating the clinical and neuropathological features associated with a previously reported pathogenic variant in RAB39B (c.503C>A p.T168K) and testing for dysregulation of RAB39B in idiopathic PD.
Methods:
Clinical details of a male individual hemizygous for the T168K variant were collected by systematic review of medical records. Neuropathological studies of fixed brain tissue were performed and steady-state RAB39B levels were determined by western blot analysis.
Results:
Neuropathological examination showed extensive dopaminergic neuron loss, widespread Lewy pathology, and iron accumulation in the substantia nigra. Additional pathology was observed in the hippocampus and thalamus. Western blot analysis demonstrated that the T168K variant results in loss of RAB39B. In individuals with idiopathic PD (n = 10, 6 male/4 female), steady-state RAB39B was significantly reduced in the prefrontal cortex and substantia nigra.
Conclusions:
T168K RAB39B is unstable in vivo and associated with dopaminergic neuron loss and Lewy pathology. Dysregulation of RAB39B in the prefrontal cortex and substantia nigra of individuals with idiopathic PD potentially implicates the protein more broadly in the pathological mechanisms underlying PD and related Lewy body disorders. © 2020 International Parkinson and Movement Disorder Society.
Insights
Pathogenic variants in Ras Analogue in Brain 39b (RAB39B) cause early-onset parkinsonism. This study found the T168K RAB39B variant leads to protein instability and dopaminergic neuron loss, with reduced RAB39B in idiopathic Parkinson's disease.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Pathogenic variants in Ras Analogue in Brain 39b (RAB39B) are linked to early-onset parkinsonism.
- The RAB39B gene encodes a small GTPase crucial for cellular function.
Purpose of the Study:
- To detail the clinical and neuropathological features of the RAB39B c.503C>A p.T168K variant.
- To investigate RAB39B dysregulation in idiopathic Parkinson's disease (PD).
Main Methods:
- Systematic review of clinical records for an individual with the T168K variant.
- Neuropathological examination of brain tissue.
- Western blot analysis to determine RAB39B levels in idiopathic PD patients.
Main Results:
- Neuropathology revealed dopaminergic neuron loss, Lewy pathology, and iron accumulation.
- The T168K variant caused RAB39B instability and loss.
- RAB39B levels were significantly reduced in the prefrontal cortex and substantia nigra of idiopathic PD patients.
Conclusions:
- The T168K RAB39B variant is unstable and associated with parkinsonism hallmarks.
- RAB39B dysregulation may play a broader role in Parkinson's disease and Lewy body disorders.
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