# The Role of Lysosomal Glucocerebrosidase in Synucleinopathies

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $559,235

## Abstract

SUMMARY
Lysosomal dysfunction has been increasingly implicated in the development of neurodegenerative diseases
including Parkinson's disease (PD). Mutations in GBA1 encoding β-glucocerebrosidase (GCase) cause
Gaucher disease (GD), the most prevalent lysosomal storage disorder and represent an important genetic risk
factor for synucleinopathies including PD and dementia with Lewy Bodies (DLB). A significant reduction in
GCase activity has been also reported in brains of sporadic PD patients, suggesting that reduced GCase
activity may represent a common feature of PD pathogenesis. Genetic linkage with PD and DLB has been also
demonstrated for lysosomal membrane protein LIMP-2, the lysosomal trafficking receptor for GCase and GD
modifier. Mutations in SCARB2 encoding LIMP-2 itself are disease-causing for a rare form of progressive
myoclonic epilepsy associated with renal failure (AMRF). Our previous data showed that loss of function of
LIMP-2 results in mistrafficking and lysosomal depletion of GCase and is also associated with a PD-like
pathology in mice. We have also demonstrated that by elevating the levels of LIMP-2, lysosomal GCase
activity was enhanced and α-syn levels reduced, suggesting that both proteins are functionally linked in the
regulation of lysosomal function and α-syn metabolism. Therefore, we hypothesize that it will be critically
important to consider LIMP-2-GCase interaction in the development of activators of GCase as potential
therapeutics for PD and related synucleinopathies. To test this hypothesis, we propose to further examine the
contribution of LIMP-2 in the pathogenesis of synucleinopathies by providing molecular insights into the
formation and trafficking of the LIMP-2/GCase complex, and its role in normal and diseased human neurons.
Aim 1 will examine the assembly and stoichiometry of the wild type LIMP-2/GCase complex in live cells by
using photoactivatable amino acids, pulse chase and immunoprecipitations experiments. These studies will be
extended to GCase and LIMP-2 patient-linked mutations to determine their impact on the formation of the
LIMP-2/GCase complex. Aim 2 will examine time-dependent phenotypes in LIMP-2- and GCase-deficient
human midbrain neurons. We will generate iPSC-derived midbrain neurons from LIMP-2 patient fibroblasts to
examine subcellular localization of GCase and GCase/LIMP-2 complex, lysosomal proteolysis and
morphology, accumulation of lipid substrates and α-synuclein in a time-dependent manner. In Aim 3 we will
perform neuropathological characterization of a mouse model expressing LIMP-2 that is deficient in binding to
GCase. To directly examine if the neurological phenotypes we previously described in LIMP-2 knockout mice
result from depletion of lysosomal GCase, we generated a mouse model expressing LIMP-2-Y163D mutant
that cannot bind GCase. These mice will be analyzed for α-syn and lipid accumulation, lysosomal dysfunction,
inflammation and neurotoxicity. These experiments will also e...

## Key facts

- **NIH application ID:** 9975946
- **Project number:** 5R01NS076054-10
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** DIMITRI KRAINC
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $559,235
- **Award type:** 5
- **Project period:** 2011-07-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975946

## Citation

> US National Institutes of Health, RePORTER application 9975946, The Role of Lysosomal Glucocerebrosidase in Synucleinopathies (5R01NS076054-10). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9975946. Licensed CC0.

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