<p>Lowe Syndrome (LS) is a lethal developmental disease
characterized by mental retardation, cataracts at birth and kidney dysfunction.
LS children unfortunately die by adolescence from renal failure. The gene
responsible for the disease (<i>OCRL1</i>) encodes an inositol 5’ phosphatase
Ocrl1. In addition to its 5’ phosphatase domain, this protein has other domains
that allow protein-protein interactions, facilitating diverse sub-cellular
distribution and functions. LS patient cells lacking Ocrl1 display defects in
cell spreading, ciliogenesis and vesicle trafficking. Currently the mechanisms
underlying these cellular defects are not known, and hence no LS-specific
therapies exist. </p>
<p>We
have uncovered the mechanisms underlying two LS-specific cellular phenotypes-
namely cell spreading and ciliogenesis and identified 2 FDA-approved candidates-
statins and rapamycin that could revert these abnormalities. We found that Ocrl1-deficient
cells exhibit hyperactivation in mTOR signaling, resulting in ciliogenesis as
well as autophagy defects, which were rescued by administering rapamycin. We
also identified a novel RhoGTPase signaling-dependent cell adhesion defect in
LS patient cells which resulted in focal adhesion abnormalities and sensitivity
to fluid shear stress (critical for kidney function). Both RhoGTPase signaling
dependent cell spreading and adhesion defects were corrected by treatment with
statins. </p>
<p>Importantly,
over 200 unique mutations in <i>OCRL1</i> cause LS and patients demonstrate
heterogeneity in symptoms. However, the correlation between genotype and
cellular phenotypes is unknown. We have determined that different <i>OCRL1</i>
patient mutations have a differential impact on the two cellular phenotypes
described above. Mutants exhibit behavior, sub-cellular distribution and
cellular phenotypes unique to the domain and relevant to LS pathogenesis. We
also propose that a subset of non-catalytic phosphatase domain mutations are
conformationally affecting the protein, suggesting that LS has a conformational
disease component. Importantly, we tested an FDA-approved drug, 4-phenyl
butyric acid (4-PBA), used as a therapeutic in conformational diseases and found
that it could revert phenotypes and restore the catalytic activity of these
mutants. These findings collectively contribute to provide the cellular basis
for LS patient heterogeneity as well as to propose a conformational disease
component for LS (allowing the use of chemical chaperones as a therapeutic
strategy for a subset of LS patients). Together, we hope that these studies
will help lay the foundation of better prognosis and tailoring personalized
therapeutic strategies for LS patients.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/12550556 |
| Date | 23 June 2020 |
| Creators | Swetha Ramadesikan (9017243) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/Role_of_Ocrl1-dependent_signaling_abnormalities_and_mutation_heterogeneity_in_Lowe_Syndrome_cellular_phenotypes/12550556 |
Page generated in 0.0017 seconds