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Review
. 2023 Mar 9:2:kvad001.
doi: 10.1093/oons/kvad001. eCollection 2023.

Genetic modifiers of synucleinopathies-lessons from experimental models

Rachel Min Qi Lee  1 , Tong-Wey Koh  1   2
Affiliations
Review

Genetic modifiers of synucleinopathies-lessons from experimental models

Rachel Min Qi Lee et al. Oxf Open Neurosci. .

Abstract

α-Synuclein is a pleiotropic protein underlying a group of progressive neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies. Together, these are known as synucleinopathies. Like all neurological diseases, understanding of disease mechanisms is hampered by the lack of access to biopsy tissues, precluding a real-time view of disease progression in the human body. This has driven researchers to devise various experimental models ranging from yeast to flies to human brain organoids, aiming to recapitulate aspects of synucleinopathies. Studies of these models have uncovered numerous genetic modifiers of α-synuclein, most of which are evolutionarily conserved. This review discusses what we have learned about disease mechanisms from these modifiers, and ways in which the study of modifiers have supported ongoing efforts to engineer disease-modifying interventions for synucleinopathies.

Keywords: Drug targets; Genetic modifiers; Lewy bodies; Parkinson’s disease; SNCA; α-synuclein.

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Conflict of interest statement

Both authors have no conflict of interest to declare.

Figures

Figure 1
Figure 1
Pathways by which genes important for mitochondrial biogenesis that modify α-syn pathology. PGC-1α, encoded by PPARGC1A, can stimulate transcription of genes for mitochondrial biogenesis. These genes are downregulated in PD brains. REST induces PGC-1α expression and is downregulated in iPSC-derived dopaminergic neurons carrying the SNCA triplication. Created with BioRender.com
Figure 2
Figure 2
Pathways by which genetic modifiers of α-syn pathology may act. Nrf2, encoded by NFE2L2, can interact with MAFK and bind to the antioxidant responsive element (ARE) to drive transcription of GCLC, encoding a subunit of GCL (glutamate cysteine ligase). GCL catalyzes the rate-limiting step in glutathione (GSH) biosynthesis. Keap1 inhibits Nrf2. ATP required for the de novo synthesis of GSH is provided for by glycolysis (green). Created with BioRender.com
Figure 3
Figure 3
Genetic modifiers of α-syn pathology from the insulin-like signaling pathway and glycolysis pathways. (A) Disruption (blue stroke) of insulin receptor (InR encoded by daf-2) in worms leads to derepression of FOXO and upregulation of PGI, both of which contribute to neuroprotection; PGI upregulation in daf-2 mutants occurs via an indirect mechanism that does not involve FOXO [106,117]. (B) Application of IGFs in mammalian cells or rodent models is neuroprotective. (C) GLP1 can potentially enhance insulin sensitivity via SIRT1 and IRS [118,119].
Figure 4
Figure 4
Pathways by which genetic modifiers of α-syn pathology may lead to cytoskeletal dysregulation, mainly by the abnormal stabilization of the actin cytoskeleton, resulting in altered mitochondrial dynamics and mitochondrial dysfunction. Created with BioRender.com
Figure 5
Figure 5
Genetic modifiers of α-syn pathology involved in membrane trafficking (green) ceramide/sphingolipid metabolism (blue). Created with BioRender.com
Figure 6
Figure 6
Pathways by which genetic modifiers of α-syn pathology may modulate α-syn spread. Created with BioRender.com
Figure 7
Figure 7
Pathways by which genetic modifiers of α-syn pathology may lead to neuroinflammatory responses such as the production of cytokine TNF-α. created with BioRender.Com
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