| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T1 |
122-196 |
DRI_Approach |
denotes |
Mutations in the co- chaperone protein, CSPα, cause an autosomal dominant, |
| T2 |
234-244 |
DRI_Approach |
denotes |
(AD-ANCL). |
| T3 |
245-412 |
DRI_Background |
denotes |
The current understanding of CSPα function exclusively at the synapse fails to explain the autophagy-lysosome pathway (ALP) dysfunction in cells from AD-ANCL patients. |
| T4 |
413-741 |
DRI_Outcome |
denotes |
Here, we demonstrate unexpectedly that primary dermal fibroblasts from pre-symptomatic mutation carriers recapitulate in vitro features found in the brains of AD-ANCL patients including auto-fluorescent storage material (AFSM) accumulation, CSPα aggregates, increased levels of lysosomal proteins and lysosome enzyme activities. |
| T5 |
742-864 |
DRI_Background |
denotes |
AFSM accumulation correlates with CSPα aggregation and both are susceptible to pharmacological modulation of ALP function. |
| T6 |
865-1038 |
DRI_Outcome |
denotes |
In addition, we demonstrate that endogenous CSPα is present in the lysosome-enriched fractions and co-localizes with lysosome markers in soma, neurites and synaptic boutons. |
| T7 |
1039-1174 |
DRI_Background |
denotes |
Overexpression of CSPα wild-type (WT) decreases lysotracker signal, secreted lysosomal enzymes and SNAP23-mediated lysosome exocytosis. |
| T8 |
1175-1314 |
DRI_Background |
denotes |
CSPα WT, mutant and aggregated CSPα are degraded mainly by the ALP but this disease-causing mutation exhibits a faster rate of degradation. |
| T9 |
1315-1412 |
DRI_Approach |
denotes |
Co-expression of both WT and mutant CSPα cause a block in the fusion of autophagosomes/lysosomes. |
| T10 |
1413-1624 |
DRI_Outcome |
denotes |
Our data suggest that aggregation-dependent perturbation of ALP function is a relevant pathogenic mechanism for AD-ANCL and supports the use of AFSM or CSPα aggregation as biomarkers for drug screening purposes. |
