Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Apoptosis / genetics
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Brain / metabolism*
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Brain / pathology
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Brain / physiopathology
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Cell Shape / genetics
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Cells, Cultured
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Genetic Predisposition to Disease / genetics*
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Humans
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Inclusion Bodies / genetics
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Inclusion Bodies / metabolism
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Inclusion Bodies / pathology
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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Lysosomes / genetics
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Lysosomes / metabolism
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Lysosomes / pathology
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Mice
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Mutation / genetics
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Nerve Degeneration / genetics
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Nerve Degeneration / metabolism*
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Nerve Degeneration / physiopathology
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Neurites / metabolism*
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Neurites / pathology
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Parkinsonian Disorders / genetics*
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Parkinsonian Disorders / metabolism
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Parkinsonian Disorders / physiopathology
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Protein Serine-Threonine Kinases / genetics*
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Rats
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Rats, Sprague-Dawley
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Substantia Nigra / metabolism
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Substantia Nigra / pathology
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Substantia Nigra / physiopathology
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tau Proteins / genetics
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tau Proteins / metabolism
Substances
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tau Proteins
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LRRK2 protein, human
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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Lrrk2 protein, mouse
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Protein Serine-Threonine Kinases