Clinical and Neuropathological Features Associated With Loss of RAB39B

Gao, Yujing; Martínez‐Cerdeño, Verónica; Hogan, Kirk; McLean, Catriona; Lockhart, Paul J.

doi:10.1002/mds.27951

Cited by 17 publications

(25 citation statements)

References 31 publications

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“…Specifically, the function(s) of RAB39B in cortical and hippocampal regions are likely to be associated with the development of cognitive impairment, whilst its function(s) in the SNpc could be linked to the development of parkinsonism. Consistent with the mouse data reported herein, we have recently demonstrated substantial steady-state levels of RAB39B in human cortex, hippocampus and substantia nigra [14]. These observations suggest the mouse represents an appropriate model for further studies to investigate the pathological mechanisms underlying parkinsonism and cognitive dysfunction in RAB39B-mediated disease.…”

Section: Discussionsupporting

confidence: 89%

Distribution of Parkinson’s disease associated RAB39B in mouse brain tissue

et al. 2020

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Pathogenic variants in the gene encoding the small GTPase Ras analogue in Brain 39b (RAB39B) are associated with early-onset parkinsonism. In this study we investigated the expression and localization of RAB39B (RNA and protein) in mouse brain tissue to gain a better understanding of its normal physiological function(s) and role in disease. We developed novel resources, including monoclonal antibodies directed against RAB39B and mice with Rab39b knockout, and performed real-time PCR and western blot analysis on whole brain lysates. To determine the spatial localization of Rab39b RNA and protein, we performed in-situ hybridization and immunohistochemistry on fresh frozen and fixed brain tissue. Our results show that RAB39B is localized throughout the cortex, hippocampus and substantia nigra of mice throughout postnatal life. We found high levels of RAB39B within MAP2 positive cortical and hippocampal neurons, and TH positive dopaminergic neurons in the substantia nigra pars compacta. Our studies support and extend current knowledge of the localization of RAB39B. We validate RAB39B as a neuronenriched protein and demonstrate that it is present throughout the mouse cortex and hippocampus. Further, we observe high levels in the substantia nigra pars compacta, the brain region most affected in Parkinson's disease pathology. The distribution of Rab39b is consistent with human disease associations with parkinsonism and cognitive impairment. We also describe and validate novel resources, including monoclonal antibodies directed against RAB39B and mice with Rab39b knockout, both of which are valuable tools for future studies of the molecular function of RAB39B.

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Section: Discussionsupporting

confidence: 89%

Distribution of Parkinson’s disease associated RAB39B in mouse brain tissue

et al. 2020

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“…Notably, we demonstrated that RAB39B is an abundant protein in dopaminergic neurons in the SNpc, the neuronal subtype selectively lost in PD. (14). These observations suggest the mouse represents an appropriate model for further studies to investigate the pathological mechanisms underlying parkinsonism and cognitive dysfunction in RAB39B-mediated disease.…”

Section: Discussionmentioning

confidence: 96%

Distribution of Parkinson’s disease associated RAB39B in mouse brain tissue

Gao

Wilson

Stephenson

et al. 2019

Preprint

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Pathogenic variants in the gene encoding the small GTPase Ras analogue in Brain 39b (RAB39B) are associated with early-onset parkinsonism. In this study we investigated the expression and localization of RAB39B (RNA and protein) in mouse brain tissue to gain a better understanding of its normal physiological function(s) and role in disease. We developed novel resources, including monoclonal antibodies directed against RAB39B and mice with Rab39b knockout, and performed real-time PCR and western blot analysis on whole brain lysates. To determine the spatial localization of Rab39b RNA and protein, we performed in-situ hybridization and immunohistochemistry on fresh frozen and fixed brain tissue. Our results show that RAB39B is localized throughout the cortex, hippocampus and substantia nigra of mice throughout postnatal life. We found high levels of RAB39B within MAP2 positive cortical and hippocampal neurons, and TH positive dopaminergic neurons in the substantia nigra pars compacta. Our studies support and extend current knowledge of the localization of RAB39B. We validate RAB39B as a neuronally-enriched protein and demonstrate that is present throughout the mouse cortex and hippocampus. Further, we observe high levels in the substantia nigra pars compacta, the brain region most affected in Parkinson’s disease pathology. The distribution of Rab39b is consistent with human disease associations with parkinsonism and cognitive impairment. We also describe and validate novel resources, including monoclonal antibodies directed against RAB39B and mice with Rab39b knockout, both of which are valuable tools for future studies of the molecular function of RAB39B.

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“…A genetic analysis of the UTRs and the regulatory regions of RAB39B has not been reported previously; our identification of a novel 5 ′ variant, with in silico predictions supporting pathogenicity, warrants further investigation. Moreover, a recent study in a small cohort of individuals with idiopathic PD suggested that steady-state levels of RAB39B in brain tissue might be decreased (34). Therefore, further genetic and functional studies are required to determine the consequences of dysregulated RAB39B expression and test its potential role as a susceptibility gene associated with PD or parkinsonism more broadly.…”

Section: Discussionmentioning

confidence: 99%

Genetic Analysis of RAB39B in an Early-Onset Parkinson's Disease Cohort

et al. 2020

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Pathogenic variants in the gene encoding RAB39B, resulting in the loss of protein function, lead to the development of X-linked early-onset parkinsonism. The gene is located within a chromosomal region that is susceptible to genomic rearrangement, and while an increased dosage of RAB39B was previously associated with cognitive impairment, the potential role of dosage alterations in Parkinson's disease (PD) remains to be determined. This study aimed to investigate the contribution of the genetic variation in RAB39B to the development of early-onset PD. We performed gene dosage studies and sequence analysis in a cohort of 176 individuals with early-onset PD (age of onset ≤50 years) of unknown genetic etiology. An assessment of the copy number variation over both coding exons and the 3 ′ untranslated region (UTR) of RAB39B did not identify any alterations in gene dosage. An analysis of the UTRs identified two male individuals carrying single, likely benign, nucleotide variants in the 3 ′ UTR (chrX:154489749-A-G and chrX:154489197-T-G). Furthermore, one novel variant of uncertain significance was identified in the 5 ′ UTR, 229 bp upstream of the start codon (chrX:154493802-C-T). In silico analyses predicted that this variant disrupts a highly conserved transcription factor binding site and could impact RAB39B expression. The results of this study do not support a significant role for genetic variation in RAB39B as contributing to early-onset PD but do highlight that additional molecular studies are required to determine the mechanisms regulating RAB39B expression and their association with the disease. Genetic investigations in larger parkinsonism/PD cohorts and longitudinal studies of individuals with cognitive impairment due to an altered dosage of RAB39B will be required to fully delineate the contribution of RAB39B to parkinsonism.

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Clinical and Neuropathological Features Associated With Loss of RAB39B

Cited by 17 publications

References 31 publications

Distribution of Parkinson’s disease associated RAB39B in mouse brain tissue

Distribution of Parkinson’s disease associated RAB39B in mouse brain tissue

Distribution of Parkinson’s disease associated RAB39B in mouse brain tissue

Genetic Analysis of RAB39B in an Early-Onset Parkinson's Disease Cohort

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