Role of Lipid Dyshomeostasis in Cognitive Dysfunction of Parkinson's Disease
Abstract
Lipid dyshomeostasis plays a prominent role in many cognitive disorders envisaging its contribution to cognitive dysfunction of Parkinsons disease (PD). Mutations in GBA that encodes glucocerebrocidase 1 (Gcase1) results in accumulation of glycosphingolipids (GSLs) leading to Gaucher disease (GD) and also the most common genetic risk factor for PD. Patients with homozygous GBA mutations exhibit PD accompanied by severe cognitive deterioration compared to sporadic cases. Even the heterozygous GBA carriers (who do not have GD) are at intermediate risk for developing cognitive dysfunction. A recent study in our lab revealed that the accumulation of glucosylceramide(GlcCer) and glucosylsphingosine (GlcSph) promotes alpha-synuclein aggregation in vitro. Additionally, a mouse line obtained by crossbreeding novel long-lived mouse model of GD (Gba L444P KO) with alpha-synuclein transgenic PD mice (SNCA tg) featured accelerated PD progression including motor abnormalities (Gba/SNCA or GD/PD mice )alongside accumulated GSLs. In this study, we are evaluating if the similar accumulation of GSLs and subsequent cellular and circuit level disturbances in the hippocampus and cortical areas drive cognitive dysfunction in GBA-associated PD. To achieve this, We are using our well-established mouse models of GD (Gba L444P KO), PD (SNCAtg) and GD/PD (Gba/SNCA) mice along with wildtype controls. Considerable amount of time was spent on establishing these mice colonies in first year.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2020
- Accession Number
- AD1115930
Entities
People
- D J Vidyadhara
Organizations
- Yale University