ABSTRACT:
Lewy body dementia is an Alzheimer’s disease–related dementia that affects more than one million Americans.
The strongest risk factor for this devastating neurodegenerative disease is mutation of the GBA gene, which
encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA mutations can impair the ability of GCase to
break down its substrate, the glycosphingolipid glucosylceramide (GlcCer), but it is not clear how defects in
GlcCer breakdown increase the risk of Alzheimer’s disease–related dementias. To study this problem, we
created a fly lacking the Drosophila ortholog of GBA, Gba1b, as a model of GCase deficiency. Our Gba1b mutant
shows accumulation of GlcCer and recapitulates features of Alzheimer’s disease–related dementias including
neurodegeneration, brain protein aggregates, and age-related cognitive decline. We now propose to use the
Gba1b mutant to test a novel model of neurodegeneration associated with GCase deficiency, in which GlcCer
accumulation leads to neuroinflammation via changes in extracellular vesicles (EVs). In earlier work, we found
that Gba1b mutants had increased abundance and turnover of EV proteins, and that genetically suppressing
neuronal EV production ameliorated mutant phenotypes. More recently, RNA-Seq experiments revealed that
Gba1b mutants had marked innate immune activation. A followup RNAi screen of major innate immune pathways
found that neuronal knockdown of two p38 MAPK pathway components, the transcription factor Atf-2 and its
upstream kinase licorne, also suppressed Gba1b mutant phenotypes. Based on these and other findings, we
hypothesize that immune-mediated neurodegeneration in Gba1b mutants is a process driven by excess GlcCer
in two separate roles. Specifically, we hypothesize that excess GlcCer in neurons triggers ligand-independent
receptor tyrosine kinase activity and p38 MAPK signaling, stimulating EV release; GlcCer in the released EVs
then causes glia to secrete immune effector proteins, leading to protein aggregation and neurodegeneration. We
propose three aims to address these hypotheses. The first will delineate the intraneuronal signaling pathway that
leads to abnormal EV release; the second will investigate the nature of the EV alterations; the third will determine
how those EVs trigger immune effector secretion from glia. Given the abundant evidence for neuroinflammation
in Alzheimer’s disease and related dementias, we anticipate that our work will have broad medical significance.