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文献入口：http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:3560775
The effect of leucine-rich repeat kinase (LRRK2) on axon and dendrite growth
and synapse development
by Sepulveda, Bryan, Ph.D., ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, 2013,
144 pages; 3560775
Abstract:
Mutations in leucine-rich repeat kinase 2 (LRRK2) underlie a form of
Parkinson's disease (PD) that is clinically indistinguishable from sporadic
PD. The function of LRRK2 is not well understood, but it has become widely
accepted that LRRK2 kinase activity, which is increased by the commonly
observed mutation (G2019S), regulates neurite length. However, it is not
known differences in length correspond to altered growth or retraction,
whether axons or dendrites are impacted differentially or whether effects
observed are transient or sustained. To address this, we compared several
developmental milestones in primary hippocampus neurons cultured from mice
overexpressing a bacterial artificial chromosome transgene overexpressing
mouse wildtype-LRRK2 (LRRK2-WTOE) or mutant LRRK2-G2019S (LRRK2-G2019SOE ),
as well as Lrrk2 knockout mice (KO) and non-transgenic mice (NT).
Over the course of three weeks of development on laminin, there is sustained
, negative effect of LRRK2-G2019SOE on dendritic growth and arborization,
but counter to expectation, dendrites from KO do not elaborate more rapidly
than NT dendrites. In contrast, young neurons cultured on a slower growth
substrate, poly-L-lysine, show significantly reduced axonal and dendritic
motility in Lrrk2 transgenic neurons and greater motility in KO neurons with
no significant changes in length. Our findings support that LRRK2 can
regulate patterns of axonal and dendritic growth, but they also show that
effects vary depending on growth substrate and stage of development.
Previous work indicated that LRRK2 has mixed effects on synapse development,
but any effect on the balance of excitatory and inhibitory connections is
unknown. LRRK2 has mixed effects on synapse development. KO neurons formed
more inhibitory appositions (GAD/gephyrin) compared to other genotypes,
while LRRK2-G2019SOE neurons formed significantly more excitatory
appositions (VGLUT/Shank) compared to other genotypes. KO neurons form
larger presynaptic SV2 clusters at 7 and 21 DIV compared to other genotypes,
indicating that KO synapses mature faster than other genotypes and that
accelerated development is sustained. Endocytosis of FM dye was equal
between genotypes, but the rate of exocytosis was greater in KO and LRRK2-
WTOE neurons. LRRK2 kinase activity negatively affects presynaptic function
while another LRRK2 function could be having a positive effect at the same
time that counteracts this.
Adviser Deanna L. Benson
School ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Source Type Dissertation
Subjects Neurosciences
Publication Number 3560775
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