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Review
. 2022 Sep;38(9):972-984.
doi: 10.1016/j.tig.2022.03.018. Epub 2022 Apr 25.

'Fly-ing' from rare to common neurodegenerative disease mechanisms

Mengqi Ma  1 , Matthew J Moulton  1 , Shenzhao Lu  1 , Hugo J Bellen  2
Affiliations
Review

'Fly-ing' from rare to common neurodegenerative disease mechanisms

Mengqi Ma et al. Trends Genet. 2022 Sep.

Abstract

Advances in genome sequencing have enabled researchers and clinicians to probe vast numbers of human variants to distinguish pathogenic from benign variants. Model organisms have been crucial in variant assessment and in delineating the molecular mechanisms of some of the diseases caused by these variants. The fruit fly, Drosophila melanogaster, has played a valuable role in this endeavor, taking advantage of its genetic technologies and established biological knowledge. We highlight the utility of the fly in studying the function of genes associated with rare neurological diseases that have led to a better understanding of common disease mechanisms. We emphasize that shared themes emerge among disease mechanisms, including the importance of lipids, in two prominent neurodegenerative diseases: Alzheimer's disease (AD) and Parkinson's disease (PD).

Keywords: Alzheimer's disease; Drosophila; Parkinson's disease; lipid; mitochondria; neurodegeneration.

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Conflict of interest statement

Declaration of interests The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.. Advantages of fly biology together with innovative genetic technologies make Drosophila melanogaster a valuable genetic tool
The fly is a valuable screening platform for random or targeted mutagenesis with visible markers and balancer chromosomes to help track mutations without the need for genotyping. The high degree of genetic conservation between human and fly genes together with humanization strategies widely available in the fly provide a useful resource to probe causes of human genetic disease. The biology of the fly, including a short lifespan, allow for simple and rapid assessment of age-dependent phenotypes including neurodegeneration.
Figure 2.
Figure 2.. Oxidated lipids produced upon neuronal ROS are shuttled to glia and sequestered in glial LD which protects neurons from damage
(A) Glial LD formation defends against neurotoxicity caused by oxidative stress in the form of ROS. Neuronal ROS production from mitochondria induces lipogenesis and lipid oxidation. Oxidated lipids are shuttled from neurons to glia where they become sequestered in LDs. (B) Loss of glial LD formation leads to neurodegeneration. Elevated ROS (due to aging, genetic risk, etc.) together with defects in neuron-to-glia lipid transfer leads to the accumulation of oxidated lipids in neurons and in the extracellular space where they induce neurodegeneration. Genes important for lipid transfer overlap with AD risk factors suggesting an important role for glial LD formation in disease.
Figure 3.
Figure 3.. The involvement of rare disease-associated genes in lipid metabolism as a common mechanism in PD
Autosomal recessive mutations in PLA2G6 are associated with INAD (PLAN). Autosomal recessive LOF alleles of GBA1 cause Gaucher disease (GD). Loss of PLA2G6 or GBA1 causes abnormal sphingolipid metabolism. Dysfunction of PLA2G6 or GBA1 causes lysosomal stress, mitochondrial defects and α-Syn aggregation, leading to the dopaminergic neuron death in PD. In addition, mitochondrial stress causes ceramide accumulation. PLIN1 regulates the homeostasis of LDs as a lipid store gatekeeper. Heterozygous frameshift mutations in PLIN1 are associated with FPLD4. Heterozygous truncating mutations in SPEN are associated with RATARS. Disruption of PLIN1 or SPEN causes accumulation of LDs, which contributes to α-Syn aggregation in the progression of PD. In addition, overexpression of α-Syn also causes LD accumulation.
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