Chen Zhang, PhD

Job Title

Postdoctoral Research Fellow

Academic Rank

Fellow or Postdoc

Department

Neurology

Authors

Jongkyun Kang (Brigham and Women's Hospital), Chen Zhang (Brigham and Women's Hospital), Yuhao Wang (Massachusetts Institute of Technology), Jian Feng (University of Illinois at Urbana-Champaign), Bonnie Berger (Massachusetts Institute of Technology), Norbert Perrimon (Harvard Medical School) and Jie Shen (Brigham and Women's Hospital)

Principal Investigator

Jie Shen

Categories

Tags

Lipophorin Receptors Genetically Modulate Neurodegeneration Caused by Psn Knockdown in the Aging Drosophila Brain

Scientific Abstract

Mutations in the Presenilin (PSEN) genes are the most common cause of early-onset familial Alzheimer’s disease (FAD). Studies in cell-free biochemical systems, cell culture, and knockin mice showed that PSEN mutations are loss-of-function mutations, impairing g-secretase activity. Mouse genetic analysis and Drosophila studies demonstrated an evolutionarily conserved role of PS in neuronal survival during aging. However, the molecular mechanisms by which PS protects neurons during aging remain unclear. To identify genetic modifiers that modulate PS-dependent neuronal survival, we developed a new Drosophila Psn model that exhibits age-dependent neurodegeneration and increases apoptosis. Following a bioinformatic analysis, we tested the top ranked 25 candidate genes by selective knockdown (KD) of each gene expression in adult neurons using two independent RNAi lines. Interestingly, neuron-specific KD of lipophorin receptors (LpR1 or LpR2) results in neurodegeneration and worsens Psn KD phenotypes. Furthermore, heterozygotic deletions of lpr1 and lpr2 or homozygotic deletions of lpr1 or lpr2 also lead to age-dependent neurodegeneration and further exacerbate neurodegeneration in Psn KD flies. These findings show that proteins involved in lipid transport and metabolism, such as LpRs, modulate Psn-dependent neuronal survival and are critically important for neuronal integrity in the aging brain.

Lay Abstract

The current study takes advantage of Drosophila genetics to look for modifiers of age-dependent neurodegeneration caused by knockdown (KD) of Psn, human orthologs of which are linked to familial Alzheimer’s disease. Among the 25 genes tested, several are involved in lipid transport and metabolism. Specifically, neuron-specific KD or germline deletions of lipophorin receptor 1 (lpr1) and/or lpr2 induced neurodegeneration and further elevated neurodegeneration caused by Psn KD, highlighting the importance of lipophorin receptors and lipid transport in Psn-dependent neuronal survival.

Clinical Implications

Our current study highlights the importance of Drosophila LDLR homologs in maintaining the integrity of the aging brain and their potent modifying effects on Presenilin dependent neurodegeneration, further supporting the importance of lipid homeostasis in neuronal survival during aging.