Journal
NEURODEGENERATIVE DISEASES
Volume 7, Issue 1-3, Pages 175-179Publisher
KARGER
DOI: 10.1159/000289232
Keywords
Leucine-rich repeat kinase 2 gene; Parkinson's disease; Lewy body disease; Progressive supranuclear gaze palsy; Nigral degeneration
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Funding
- Pacific Alzheimer Research Foundation [C06-01]
- CIHR [121849]
- Swiss National Science Foundation [PASMP3-123268/1]
- [P01 AG017216]
- [R01 NS057567]
- [R01 AG015866]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS057567, P01NS040256, P50NS040256] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [P01AG017216, R01AG015866] Funding Source: NIH RePORTER
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Background: Leucine-rich repeat kinase 2 (LRRK2) has emerged as the most prevalent genetic cause of Parkinson's disease (PD) among Caucasians. Patients carrying an LRRK2 mutation display significant variability of clinical and pathologic phenotypes across and within affected families. Methods: Herein, we review available clinical and pathologic data on patients with an LRRK2 mutation who have come to autopsy. Results: Thirty-eight patients have been reported who presented clinically with PD; parkinsonism with resistance to levodopa, supranuclear gaze palsy, or autonomic dysfunction; or tremor and dementia. Pathology showed typical PD-type Lewy body disease (LBD) in most patients, whereas in others there was 'pure' nigral degeneration (one with TDP-43-positive inclusions), diffuse LBD, or tau-, alpha-synuclein- or ubiquitin-positive pathology reminiscent of progressive supranuclear gaze palsy, multisystem atrophy, and frontotemporal dementia with ubiquitin-positive inclusions. Conclusions: Such clinical and pathologic variability suggests Lrrk2 acts upstream from other proteins implicated in neurodegeneration. Specific mutations may be associated with alternative progressive supranuclear gaze palsy-like or 'pure' nigral degeneration phenotypes. A different effect on Lrrk2 kinase activity may play a role in such heterogeneity. Copyright (C) 2010 S. Karger AG, Basel
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