Objective: Elucidate the mechanisms underlying pathogenesis of X-linked Parkinson’s disease (PD) due to the RAB39B p.G192R mutation.

Background: RAB39B p.G192R causes X-linked PD with decreased penetrance in females (Mata I, et al. 2015). Rab39b encodes a neuronal Ras family GTPase with a role in early autophagosome formation; it localizes to early endosomes and is implicated in vesicular trafficking. Rab39b is highly conserved in both vertebrates and invertebrates. A large kindred with X-linked PD due to the p.G192R variant was ascertained. Two deceased affected family members with clinically typical PD underwent neuropathological analysis. One had tauopathy with no Lewy body co-pathology, while the other had both tau and extensive (neocortical stage) Lewy body pathology.

Method: We generated human induced pluripotent stem cells (iPSCs) from an affected male with PD and a similar age unaffected male sibling from this kindred. Dopaminergic neurons were differentiated from iPSCs and analyzed by western blot and immunocytochemistry for markers of endolysosomal trafficking. Tau and alpha-synuclein (a-syn) aggregation were evaluated by western blot of neuronal cell lysates.

Results: In dopaminergic neurons differentiated from iPSCs, RAB39B protein levels were slightly reduced in RAB39B-192R neurons compared to controls. Western blotting of RAB39B-192R neurons revealed increased a-syn oligomers and tau aggregates (AT8 antibody) compared to control neurons. There was no change in EEA1 levels, a marker for early endosomes, in RAB39B-192R neurons compared to controls. However, Rab11 (a marker of recycling endosomes) and LAMP1 (a marker of late endosomes and lysosomes), were increased in RAB39B-192R neurons.

Conclusion: RAB39B p.G192R X-linked Parkinson’s disease can manifest neuropathologically as both tauopathy and Lewy pathology, indicating that RAB39B is important for the pathogenesis of tau and synuclein co-pathologies. Our iPSC-neuron model also supports this and indicates that RAB39B is important in late endolysosomal trafficking. Elucidating how RAB39B can cause both tau and synuclein pathology will improve our ability to therapeutically target co-pathology.

References: Mata IF, Jang Y, Kim CH, Hanna DS, Dorschner MO, Samii A, Agarwal P, Roberts JW, Klepitskaya O, Shprecher DR, Chung KA, Factor SA, Espay AJ, Revilla FJ, Higgins DS, Litvan I, Leverenz JB, Yearout D, Inca-Martinez M, Martinez E, Thompson TR, Cholerton BA, Hu SC, Edwards KL, Kim KS, Zabetian CP. The RAB39B p.G192R mutation causes X-linked dominant Parkinson’s disease. Mol Neurodegener. 2015 Sep 24;10:50. doi: 10.1186/s13024-015-0045-4. PMID: 26399558; PMCID: PMC4581468.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/elucidating-tau-and-alpha-synuclein-co-pathology-in-rab39b-x-linked-parkinsons-disease/