LRRK2 knockdown in zebrafish causes developmental defects, neuronal loss, and synuclein aggregation.
Although mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of genetic Parkinson's disease, their function is largely unknown. LRRK2 is pleiotropic in nature, shown to be involved in neurodegeneration and in more peripheral processes, including kidney functions, in rats and mice. Recent studies in zebrafish have shown conflicting evidence that removal of the LRRK2 WD40 domain may or may not affect dopaminergic neurons and/or locomotion. This study shows that ∼50% LRRK2 knockdown in zebrafish causes not only neuronal loss but also developmental perturbations such as axis curvature defects, ocular abnormalities, and edema in the eyes, lens, and otic vesicles. We further show that LRRK2 knockdown results in significant neuronal loss, including a reduction of dopaminergic neurons. Immunofluorescence demonstrates that endogenous LRRK2 is expressed in the lens, brain, heart, spinal cord, and kidney (pronephros), which mirror the LRRK2 morphant phenotypes observed. LRRK2 knockdown results further in the concomitant upregulation of β-synuclein, PARK13, and SOD1 and causes β-synuclein aggregation in the diencephalon, midbrain, hindbrain, and postoptic commissure. LRRK2 knockdown causes mislocalization of the Na(+) /K(+) ATPase protein in the pronephric ducts, suggesting that the edema might be linked to renal malfunction and that LRRK2 might be associated with pronephric duct epithelial cell differentiation. Combined, our study shows that LRRK2 has multifaceted roles in zebrafish and that zebrafish represent a complementary model to further our understanding of this central protein. © 2016 Wiley Periodicals, Inc.
Department of Biological Sciences, St. John's University, Queens, New York.
Shubhangi
S
Prabhudesai
Department of Biological Sciences, St. John's University, Queens, New York.
Fatima Zahra
FZ
Bensabeur
Department of Biological Sciences, St. John's University, Queens, New York.
Rashed
R
Abdullah
Department of Biological Sciences, St. John's University, Queens, New York.
Indranil
I
Basak
Department of Biological Sciences, St. John's University, Queens, New York.
Solange
S
Baez
The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
Guido
G
Alves
Department of Biology, Queens College and The Graduate Center, CUNY, Queens, New York.
Nathalia G
NG
Holtzman
The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
Jan Petter
JP
Larsen
Department of Biological Sciences, St. John's University, Queens, New York.|The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
Simon Geir
SG
Møller
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology*; D000595:Amino Acid Sequence; D000818:Animals; D001923:Brain Chemistry / Q000235:genetics; D059290:Dopaminergic Neurons; D055785:Gene Knockdown Techniques; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000096:biosynthesis / Q000235:genetics*; D008124:Locomotion; D009154:Mutation / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D010300:Parkinson Disease / Q000235:genetics; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000096:biosynthesis / Q000235:genetics*; D051846:beta-Synuclein / Q000235:genetics*
D029961:Zebrafish Proteins; D051846:beta-Synuclein; C551314:LRRK2 protein, zebrafish; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D000254:Sodium-Potassium-Exchanging ATPase
LRRK2; Parkinson's disease; development; kidneys; zebrafish