Transcription factor EB overexpression prevents neurodegeneration in experimental synucleinopathies

Introduction Synucleinopathies are a heterogenous group of neurodegenerative diseases characterized by the formation of α-synuclein (α-syn) aggregates. Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease and is characterized by motor and nonmotor symptoms. The motor symptomatology is mainly associated with profound dopamine depletion in the striatum due to the loss of mesencephalic dopaminergic neurons. The main neuropathological hallmark of PD is the presence of neu-ronal α-syn-positive intracytoplasmic inclusions named Lewy bodies (LB) in cell bodies and Lewy neurites in cell processes (1). Multiple system atrophy (MSA) is a rare, fast-progressing disease divided in 2 clinical phenotypes: (a) the MSA parkinsonian showing L-3,4-dihydroxyphenylalanine nonresponsive parkinso-nian syndrome with bradykinesia, rigidity, and rest tremor due to a dopaminergic loss in the nigrostriatal pathway; and (b) the MSA cerebellar exhibiting cerebellar syndrome with gait, speech, and limb ataxia, and cerebellar oculomotor dysfunction caused by a neuronal loss in the olivopontocerebellar pathway. The neuropathological hallmark of MSA is the presence of α-syn-positive cytoplasmic inclusions, in oligoden-drocytes, named glial cytoplasmic inclusions (2). The presence of α-syn-positive aggregates suggests that a defect in α-syn degradation could play a role in the accumulation of the aggregated and misfolded proteins in these neurodegenerative disorders (3, 4). α-Syn degradation is ensured by the 2 protein degradation pathways: the ubiquitin-proteasome system (5) and the autophagy-lysosomal pathways (ALP) through both macroautophagy and chaperone-mediated autophagy (6-9). The ALP is a versatile cellular proteolytic system allowing the degradation of long-lived protein, protein aggregates, and abnormal organelles-among other cellular waste-through different mechanisms (10). The synucleinopathies Parkinson's disease (PD) and Multiple system atrophy (MSA)-characterized by α-synuclein intracytoplasmic inclusions into, respectively, neurons and oligodendrocytes-are associated with impairment of the autophagy-lysosomal pathways (ALP). Increased expression of the master regulator of ALP, transcription factor EB (TFEB), is hypothesized to promote the clearance of WT α-synuclein and survival of dopaminergic neurons. Here, we explore the efficacy of targeted TFEB overexpression either in neurons or oligodendrocytes to reduce the pathological burden of α-synuclein in a PD rat model and a MSA mouse model. While TFEB neuronal expression was sufficient to prevent neurodegeneration in the PD model, we show that only TFEB oligodendroglial overexpression leads to neuroprotective effects in the MSA model. These beneficial effects were associated with a decreased accumulation of α-synuclein into oligodendrocytes through recovery of the ALP machinery. Our study demonstrates that the cell type where α-synuclein aggregates dictates the target of TFEB overexpression in order to be protective, paving the way for adapted therapies.