The familial Parkinsonism gene LRRK2 regulates neurite process morphology.
Mutations in LRRK2 underlie an autosomal-dominant, inherited form of Parkinson's disease (PD) that mimics the clinical features of the common "sporadic" form of PD. The LRRK2 protein includes putative GTPase, protein kinase, WD40 repeat, and leucine-rich repeat (LRR) domains of unknown function. Here we show that PD-associated LRRK2 mutations display disinhibited kinase activity and induce a progressive reduction in neurite length and branching both in primary neuronal cultures and in the intact rodent CNS. In contrast, LRRK2 deficiency leads to increased neurite length and branching. Neurons that express PD-associated LRRK2 mutations additionally harbor prominent phospho-tau-positive inclusions with lysosomal characteristics and ultimately undergo apoptosis.
MacLeod
David
D
Departments of Pathology and Neurology, Center for Neurobiology and Behavior and Taub Institute, Columbia University, College of Physicians and Surgeons 15-403, 630 West 168th Street, New York, New York 10032, USA.
Dowman
Julia
J
Hammond
Rachel
R
Leete
Thomas
T
Inoue
Keiichi
K
Abeliovich
Asa
A
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D048430:Cell Shape / Q000235:genetics; D002478:Cells, Cultured; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016501:Neurites / Q000378:metabolism* / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D016875:tau Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases