Objective: To explore the potential neuroprotective effects of overexpressing the transcription factor EB in a MSA mouse model .

Background: Synucleinopathies are neurodegenerative diseases characterized by the presence of α-synuclein-positive intracytoplasmic inclusions into the central nervous system. Increasing evidence indicates that impairment of lysosomal function may contribute to the pathogenesis of the synucleinopathies, including Parkinson’s Disease (PD) and Multiple system atrophy (MSA). The transcription factor EB (TFEB) is a master gene of lysosomal biogenesis which coordinates the expression of lysosomal genes leading to an induction of autophagy. It has been demonstrated that overexpressing TFEB in a rat parkinsonian model triggers the restauration of the lysosomal machinery which leads to an enhancement in the clearance of α-synuclein, finally leading to neuroprotective effects [1].

Method: We used a transgenic mouse model of MSA, the PLP-Syn mouse model, which overexpresses the human wild-type-α-synuclein in oligodendrocytes under the mouse myelin proteolipid protein (PLP) promoter. By combining a viral-based approach to overexpress TFEB under a neuronal or an oligodendroglial promoter, we investigated the effects of cell-specific targeting TFEB overexpression on neurodegeneration, α-synuclein clearance and lysosomal machinery using both histochemical and biochemical approaches five months following intranigral injection in this mouse model of MSA.

Results: We provide evidence that only specific oligodendroglial overexpression of TFEB leads to neuroprotective effects associated with an increased clearance of the protein α-synuclein into the oligodendrocytes after autophagic machinery recovery with increased lysosome biogenesis and lysosomal activity. We also confirmed the neurotrophic effects induced by TFEB overexpression in this MSA mouse model. In addition, we observed defects in TFEB expression levels in MSA patient brains, pointing TFEB as a relevant and attractive therapeutic target for MSA.

Conclusion: These results reinforce the ability of using viral-mediated TFEB gene expression to regulate lysosomal biogenesis and activity as a powerful therapeutic approach in synucleinopathies such as PD and MSA by targeting its expression specifically into damaged cellular types according to the pathology.

References: [1] Decreassac and al., TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity, PNAS (2013). doi: 10.1073/pnas.1305623110

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MDS Abstracts - https://www.mdsabstracts.org/abstract/tfeb-driven-expression-prevents-neurodegeneration-in-a-multiple-system-atrophy-mouse-model/