| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T1 |
77-189 |
DRI_Approach |
denotes |
Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most common genetic cause of PD (Parkinson's disease). |
| T2 |
190-336 |
DRI_Approach |
denotes |
To investigate how mutations in LRRK2 cause PD, we generated LRRK2 mutant mice either lacking its expression or expressing the R1441C mutant form. |
| T3 |
337-720 |
DRI_Background |
denotes |
Homozygous R1441C knockin mice exhibit no dopaminergic neurodegeneration or alterations in steady-state levels of striatal dopamine, but they show impaired dopamine neurotransmission, as was evident from reductions in amphetamine-induced locomotor activity and stimulated catecholamine release in cultured chromaffin cells as well as impaired dopamine D2 receptor-mediated functions. |
| T4 |
721-1013 |
DRI_Background |
denotes |
Whereas LRRK2-/- brains are normal, LRRK2-/- kidneys at 20 months of age develop striking accumulation and aggregation of α-synuclein and ubiquitinated proteins, impairment of the autophagy-lysosomal pathway, and increases in apoptotic cell death, inflammatory responses and oxidative damage. |
| T5 |
1014-1236 |
DRI_Approach |
denotes |
Our further analysis of LRRK2-/- kidneys at multiple ages revealed unique age-dependent biphasic alterations of the autophagic activity, which is unchanged at 1 month of age, enhanced at 7 months, but reduced at 20 months. |
| T6 |
1237-1375 |
DRI_Background |
denotes |
Levels of α-synuclein and protein carbonyls, a general oxidative damage marker, are also decreased in LRRK2-/- kidneys at 7 months of age. |
| T7 |
1376-1565 |
DRI_Challenge |
denotes |
Interestingly, this biphasic alteration is associated with increased levels of lysosomal proteins and proteases as well as progressive accumulation of autolysosomes and lipofuscin granules. |
| T8 |
1566-1750 |
DRI_Outcome |
denotes |
We conclude that pathogenic mutations in LRRK2 impair the nigrostriatal dopaminergic pathway, and LRRK2 plays an essential role in the dynamic regulation of autophagy function in vivo. |
