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.
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.
Authors: Stuart J McCarter; Elizabeth A Coon; Rodolfo Savica; Erik K St Louis; James H Bower; Eduardo E Benarroch; Paola Sandroni; Phillip Low; Wolfgang Singer Journal: Mov Disord Date: 2020-04-22 Impact factor: 10.338
Authors: Alessandra Fanciulli; Fabian Leys; Fabienne Lehner; Victoria Sidoroff; Viktoria C Ruf; Cecilia Raccagni; Philipp Mahlknecht; Demy J S Kuipers; Wilfred F J van IJcken; Heike Stockner; Thomas Musacchio; Jens Volkmann; Camelia Maria Monoranu; Iva Stankovic; Guido Breedveld; Federico Ferraro; Christina Fevga; Otto Windl; Jochen Herms; Stefan Kiechl; Werner Poewe; Klaus Seppi; Nadia Stefanova; Sonja W Scholz; Vincenzo Bonifati; Gregor K Wenning Journal: Brain Commun Date: 2022-07-04
Authors: Carla Azevedo; Gabriel Teku; Yuriy Pomeshchik; Juan F Reyes; Margarita Chumarina; Kaspar Russ; Ekaterina Savchenko; Anna Hammarberg; Nuno Jorge Lamas; Anna Collin; Gunnar K Gouras; Oxana Klementieva; Martin Hallbeck; Ricardo Taipa; Mauno Vihinen; Laurent Roybon Journal: Proc Natl Acad Sci U S A Date: 2022-03-16 Impact factor: 11.205