Περίληψη:
Background
Despite the plethora of sequence variants in LRRK2, only a few clearly
segregate with PD. Even within this group of pathogenic mutations, the
phenotypic profile can differ widely.
Objective
We examined multiple properties of LRRK2 behavior in cellular models
over-expressing three sequence variants described in Greek PD patients
in comparison to several known pathogenic and non-pathogenic LRRK2
mutations, to determine if specific phenotypes associated with
pathogenic LRRK2 can be observed in other less-common sequence variants
for which pathogenicity is unclear based on clinical and/or genetic data
alone.
Methods
The oligomerization, activity, phosphorylation, and interaction with
FADD was assessed in HEK293T cells over-expressing LRRK2; while the
induction of neuronal death was determined by quantifying apoptotic
nuclei in primary neurons transiently expressing LRRK2.
Results
One LRRK2 variant, A211V, exhibited a modest increase in kinase
activity, whereas only the pathogenic mutants G2019S and I2020T
displayed significantly altered auto-phosphorylation. We observed an
induction of detergent-insoluble high molecular weight structures upon
expression of pathogenic LRRK2 mutants, but not the other LRRK2
variants. In contrast, each of the variants tested induced apoptotic
death of cultured neurons similar to pathogenic LRRK2 in a
FADD-dependent manner.
Conclusions
Overall, despite differences in some properties of LRRK2 function such
as kinase activity and its oligomerization, each of the LRRK2 variants
examined induced neuronal death to a similar extent. Furthermore, our
findings further strengthen the notion of a convergence on the extrinsic
cell death pathway common to mutations in LRRK2 that are capable of
inducing neuronal death.
Συγγραφείς:
Melachroinou, Katerina
Leandrou, Emmanouela
Valkimadi,
Polytimi-Eleni
Memou, Anna
Hadjigeorgiou, Georgios
Stefanis,
Leonidas
Rideout, Hardy J.
