We have recently shown that the small GTPase Rab12, which was previously shown to control housekeeping
functions, such as autophagy and iron regulation1,2, negatively regulates degranulation of mast
cells (MCs), by binding and recruiting the RILP-dynein motor complex to the MC secretory granules
(SGs), and driving their retrograde transport, thus restricting degranulation3. These results have
marked the Rab12-RILP complex as an important regulator of allergy, mast cell-dependent
inflammation, and other processes that rely on Rab12-regulated retrograde transport. We and
others have also shown that Rab12 additionally binds the two other members of the RILP family, RILPLike
1 (RILP-L1) and RILP-Like 2 (RILP-L2), whose precise functions are presently unknown, yet
distinct from RILP, as neither RILP-L1, nor RILP-L2 bind the motor protein dynein. Rab12 has been
recently identified as a physiological substrate of the leucine-rich-repeat kinase 2 (LRRK2),
mutations in which comprise the most common cause of familial Parkinson’s disease (PD) and
gene polymorphism either positively or negatively correlate with PD risk. LRRK2 has also been
implicated in inflammatory diseases including: leprosy, tuberculosis and inflammatory bowel diseases.
In particular, GWAS has identified LRRK2 as a major susceptibility gene for Crohn’s disease.
Finally, mutations in Rab12 were found in patients with task-specific movement disorders.
Phosphorylated Rab12 preferably interacts with its effector proteins: RILP-L1 and RILP-L2. Therefore,
we propose that impaired balance of Rab12-effector interactions, contributes to Rab12-involved
disease, such as in the case of hyperactivation of LRRK2, leading to hyperphosphorylation of Rab12.
Included in this category are PD pathogenesis in the CNS, inflammation in the immune system, and
other diseases linked with LRRK2 or Rab12.
UNMET NEED
Tools to restore the impaired balance of Rab12 connectivity, to restore Rab12 controlled
distribution between its complexes with RILP, RILP-L1 or RILP-L2, as treatment for Rab12-
involved disease.
OUR SOLUTION
Peptides4, or small molecules designed to manipulate Rab12 connectivity by inhibiting exaggerated
complex formation due to hyperphosphorylation of Rab12, or stimulating formation of complexes
whose formation is reduced due to hyperphosphorylation of Rab12.
OUR PRODUCT
Peptides or small molecules
PATENTS
U.S. Provisional Patent Application entitled “Compositions and methods for regulating Rab12
function and/or interactions with related proteins and use thereof in diseases in which Rab12 function
and/or interactions with other proteins are impaired” was filed on 11 February 2021.