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 Parkinson's 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 PDmice (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. We performed both motor and cognitive behavior assays longitudinally at 3, 6 and 9 months of age on these mice. Motor behavior analysis indicate GD/PD mice to have a severe progressive motor deficit compared GD mice. Results of cognitive behavior assay are being analyzed. We standardized immunohistochemistry, confocal microscopy and image analysis methods as well as collected and stored the mice brain specimens at appropriate age for upcoming experiments.

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Document Details

Document Type
Technical Report
Publication Date
Aug 01, 2021
Accession Number
AD1149338

Entities

People

  • D J Vidyadhara

Organizations

  • Yale University

Tags

DTIC Thesaurus Topics

  • Animal Structures
  • Biomedical Research
  • Computer Vision
  • Covid-19
  • Data Analysis
  • Data Science
  • Diseases And Disorders
  • Dysfunction
  • Genetics
  • Glycolipids
  • Health
  • Immunohistochemistry
  • Lipids
  • Medical Personnel
  • Microscopy
  • Object Recognition
  • Parkinson'S Disease
  • Pathology
  • Professional Development
  • Students
  • Therapy
  • Universities

Fields of Study

  • Biology

Readers

  • Molecular and Cellular Biology
  • Neurodegenerative Parkinson's Disease and Rickettsial Disease handbook, including the data level of dopamine, BC, neurons, and PD.
  • Team-Based Human-Centered Cognitive Task Decision Making and Information Performance.

Technology Areas

  • Biotechnology
  • Biotechnology - Cancer Biotech