Leucine-rich repeat kinase 2 colocalizes with alpha-synuclein in Parkinson's disease, but not tau-containing deposits in tauopathies.
BACKGROUND
Mutations in leucine-rich repeat kinase 2 (LRRK2) are thus far the most frequent genetic cause associated with autosomal dominant and idiopathic Parkinson's disease.


OBJECTIVE
To examine whether LRRK2 is directly associated with the pathological structures of Parkinson's disease, dementia with Lewy bodies, and other related disorders using highly specific antibodies to LRRK2.


RESULTS
LRRK2 antibodies strongly labeled brainstem and cortical Lewy bodies, the pathological hallmarks of Parkinson's disease and dementia with Lewy bodies, respectively. We found that 20-100% (mean 60%) of alpha-synuclein-positive Lewy bodies contained LRRK2. While antibodies raised against various regions of LRRK2 were previously shown to label recombinant LRRK2 on Western blots, only antibodies raised against the N- and C-termini, but not the regions containing folded protein domains of LRRK2, immunolabeled Lewy bodies. In Alzheimer's disease, Hirano bodies were found to contain LRRK2 and the neurofibrillary tangles in progressive supranuclear palsy remained unlabeled.


CONCLUSIONS
Information on the cellular localization of LRRK2 under normal and pathological conditions will deepen our understanding of its functions and molecular pathways relevant to the progression of Parkinson's disease and related disorders.
Perry
George
G
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA. george.perry@utsa.edu
Zhu
Xiongwei
X
Babar
Asim K
AK
Siedlak
Sandra L
SL
Yang
Qiwei
Q
Ito
Genta
G
Iwatsubo
Takeshi
T
Smith
Mark A
MA
Chen
Shu G
SG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001923:Brain Chemistry / Q000502:physiology; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008875:Middle Aged; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism*; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology*; D051844:alpha-Synuclein / Q000032:analysis / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D051844:alpha-Synuclein; D016875:tau Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases