LRRK2 p.Ile1371Val Mutation in a Case with Neuropathologically Confirmed Multi-System Atrophy

Article type: Research Article

Authors: Lee, Kelsey^a | Nguyen, Khanh-Dung^b | Sun, Chao^b | Liu, Mei^b | Zafar, Faria^a | Saetern, Jimmy^a | Flierl, Adrian^a | Tetrud, James W.^c | Langston, J. William^a | Dickson, Dennis^d | Schüle, Birgitt^{a; *}

Affiliations: [a] Parkinson’s Institute and Clinical Center, Sunnyvale, CA, USA | [b] Biogen, Cambridge, MA, USA | [c] Stanford Neuroscience Health Center, Stanford School of Medicine, Stanford, CA, USA | [d] Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA

Correspondence: [*] Correspondence to: Birgitt Schüle, MD, Dr. med., Parkinson’s Institute and Clinical Center, 675 Almanor Ave, Sunnyvale, CA 94085, USA. Tel.: +1 408 542 5611; Fax: +1 408 734 8455; E-mail: [email protected]

Abstract: Background:Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are among the most common genetic causes of Lewy body Parkinson’s disease (PD). However, LRRK2 mutations can also lead to a variety of pathological phenotypes other than typical PD, including relatively pure nigrostriatal cell loss without alpha-synuclein-positive Lewy bodies or Lewy neurites, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). The mechanisms behind this remarkable pleomorphic pathology are currently unclear. Objective:To genetically and pathologically characterize a case with a LRRK2, p.Ile1371Val rare variant and pathologically proven MSA. Methods:From the brain donation program at the Parkinson’s Institute and Clinical Center, we selected 26 brains with family history and a with clinicopathological diagnosis of PD (n = 20), MSA (n = 4), or PSP (n = 2). We performed neuropathological evaluation, including alpha-synuclein and tau immunohistochemistry and sequenced 188 genes that have been reported as causative for or associated with neurodegenerative diseases. Results:We identified a known LRRK2, p.Ile1371Val genetic variant in a case with clinically diagnosed and pathologically proven MSA. Neuropathology revealed that the olivopontocerebellar system was more affected than the striatonigral system. Conclusions:Our data suggest that genetic variants in the LRRK2 gene can present clinically and neuropathologically as MSA. One other LRRK2 genetic variant (LRRK2, p.Ile2020Thr) has been reported with a neuropathological diagnosis of MSA. Interestingly, the LRRK2 variant (LRRK2, p.Ile1371Val) identified here has been reported previously in a postmortem case with Lewy body PD.Future studies are critical to discover the mechanisms leading to different neurodegenerative trajectories both in neuronal and glial cell populations.

Keywords: Alpha-synuclein, genetic risk factor, glial cytoplasmic inclusions, leucine-rich repeat kinase 2, LRRK2, multiple system atrophy, mutation, neuronal cytoplasmic inclusions, olivopontocerebellar degeneration, p.Ile1371Val

DOI: 10.3233/JPD-171237

Journal: Journal of Parkinson's Disease, vol. 8, no. 1, pp. 93-100, 2018