Heterogenous Neuropathology in a Pedigree with RAB39B-Related Parkinson's Disease

In 2015, we reported a family with Parkinson's disease resulting from the RAB39B p.G192R (c.574G>A) variant. Since then, two affected brothers from the family have undergone autopsy.

To characterize neuropathological findings, assess intracellular distribution of RAB39B protein, and examine the effect of p.G192R on α-synuclein and tau.

Detailed neuropathological assessments were performed on both siblings. Dopaminergic neurons were generated from induced pluripotent stem cells (iPSCs) from an affected and unaffected male in this kindred. Western blots were performed to measure RAB39B, α-synuclein, phospho-α-synuclein, and phospho-tau.

The younger brother had neocortical stage Lewy body disease (LBD) pathology and an unusual pattern and burden of four-repeat (4R) tau pathology that included neocortical neurofibrillary tangles, pretangles, and neurites in the absence of β-amyloid pathology. The older brother's brain showed a similar pattern of 4R tau pathology but had no LBD pathology. Robust RAB39B immunostaining was seen in p.G192R carriers and non-carriers. In p.G192R iPSC-derived neurons, RAB39B protein was reduced by ~50% and disproportionately diminished in peripheral cell processes compared with cell bodies. Aberrant forms of both α-synuclein and tau were observed in p.G192R neurons.

The intrafamilial pathological heterogeneity observed here is unusual for monogenic parkinsonism and suggests that mechanisms underlying RAB39B-related neurodegeneration might be complex. Our results from iPSC-neurons provide additional support that RAB39B p.G192R promotes α-synuclein and tau co-pathology. Further work in model systems based on RAB39B p.G192R might offer important insights into the interplay between α-synuclein and tau that are applicable to multiple neurodegenerative disorders. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.