Yujing Gao1,2, Verónica Martínez-Cerdeño3,4, Kirk J Hogan5,6, Catriona A McLean7, Paul J Lockhart1,2. 1. Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Parkville, Victoria, Australia. 2. Department of Pediatrics, The University of Melbourne, Melbourne, Victoria, Australia. 3. Department of Pathology and Laboratory Medicine, UC Davis School of Medicine; Institute for Pediatric Regenerative Medicine and Shriners Hospitals for Children of Northern California, Davis, California, USA. 4. MIND Institute, UC Davis Medical Center, Davis, California, USA. 5. Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA. 6. Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA. 7. Anatomical Pathology, Alfred Hospital, Melbourne, Victoria, Australia.
Abstract
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.
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.
Authors: Daniel Erskine; David Koss; Viktor I Korolchuk; Tiago F Outeiro; Johannes Attems; Ian McKeith Journal: Acta Neuropathol Date: 2021-01-30 Impact factor: 17.088
Authors: Yujing Gao; Gabrielle R Wilson; Sarah E M Stephenson; Mustapha Oulad-Abdelghani; Nicolas Charlet-Berguerand; Kiymet Bozaoglu; Catriona A McLean; Paul Q Thomas; David I Finkelstein; Paul J Lockhart Journal: Mol Brain Date: 2020-03-30 Impact factor: 4.041
Authors: David J Koss; Odeta Bondarevaite; Sara Adams; Marta Leite; Flaviano Giorgini; Johannes Attems; Tiago F Outeiro Journal: Brain Pathol Date: 2020-08-25 Impact factor: 7.611