Abnormal localization of leucine-rich repeat kinase 2 to the endosomal-lysosomal compartment in lewy body disease.
Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common causes of both familial and sporadic forms of Parkinson disease and are also associated with diverse pathological alterations. The mechanisms whereby LRRK2 mutations cause these pathological phenotypes are unknown. We used immunohistochemistry with 3 distinct anti-LRRK2 antibodies to characterize the expression of LRRK2 in the brains of 21 subjects with various neurodegenerative disorders and 7 controls. The immunoreactivity of LRRK2 was localized in a subset of brainstem-type Lewy bodies (LBs) but not in cortical-type LBs, tau-positive inclusions, or TAR-DNA-binding protein-43-positive inclusions. The immunoreactivity of LRRK2 frequently appeared as enlarged granules or vacuoles within neurons of affected brain regions, including the substantia nigra, amygdala, and entorhinal cortex in patients with Parkinson disease or dementia with LBs. The volumes of LRRK2-positive granular structures in neurons of the entorhinal cortex were significantly increased in dementia with LBs brains compared with age-matched control brains (p < 0.05). Double immunolabeling demonstrated that these LRRK2-positive granular structures frequently colocalized with the late-endosomal marker Rab7B and occasionally with the lysosomal marker, the lysosomal-associated membrane protein 2. These results suggest that LRRK2 normally localizes to the endosomal-lysosomal compartment within morphologically altered neurons in neurodegenerative diseases, particularly in the brains of patients with LB diseases.
Higashi
Shinji
S
PET/CT Dementia Research Center, Juntendo Tokyo Koto Geriatric Medical Center, Juntendo University School of Medicine, Koto-ku, Tokyo, Japan. higashis@ncnp.go.jp
Moore
Darren J
DJ
Yamamoto
Ryoko
R
Minegishi
Michiko
M
Sato
Kiyoshi
K
Togo
Takashi
T
Katsuse
Omi
O
Uchikado
Hirotake
H
Furukawa
Yoshiko
Y
Hino
Hiroaki
H
Kosaka
Kenji
K
Emson
Piers C
PC
Wada
Keiji
K
Dawson
Valina L
VL
Dawson
Ted M
TM
Arai
Heii
H
Iseki
Eizo
E
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D003704:Dementia / Q000378:metabolism / Q000473:pathology; D011992:Endosomes / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D020774:Pick Disease of the Brain / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D013494:Supranuclear Palsy, Progressive / Q000378:metabolism / Q000473:pathology
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
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