In vivo modulation of REST/NRSF as a therapeutic target for Parkinson "s Disease"
In vivo modulation of REST/NRSF as a therapeutic target for Parkinson "s Disease"
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Original abstract
Parkinson¿s disease (PD) is a progressive neurodegenerative disorder marked bydopaminergic neuron loss in the substantia nigra (SN) and pathological accumulation of ¿-synuclein. The transcriptional repressor RE1-Silencing Transcription Factor (REST) hasbeen implicated in neuronal stress resistance, yet its in vivo role in midbrain dopaminergicneurons remains unclear. This thesis investigated the effects of REST overexpression in thesubstantia nigra pars compacta (SNc) and ventral tegmental area (VTA) under physiologicaland pathological conditions using AAV-mediated delivery and two complementary PDmouse models: the ¿-synuclein pre-formed fibril (PFF) model and the SNCAoverexpressing(SNCA-OVX) transgenic model. REST was selectively overexpressed indopaminergic neurons using AAV2/9 vectors across a range of titration doses. REST effectswere strongly dose-dependent. Low-dose expression (2.5×10¹¹ GC/ml) achieved targetedexpression in TH+ neurons with minimal toxicity, whereas high-dose REST (2.5×10¹²GC/ml) induced motor impairments, reduced TH+ neuron numbers, and off-targetexpression, indicating disruption of dopaminergic function and emphasizing the need forprecise expression control. At controlled levels, REST exerted neuroprotective effects,including improved mitochondrial morphology and abundance, reflected by increasedVDAC expression in both SNc and VTA. REST also facilitated ¿-synuclein clearance in adose-dependent manner and modulated autophagy-lysosomal pathway markers, suggestingmodel- and stage-specific regulation of protein degradation mechanisms. Transcriptomicanalyses revealed that REST counteracted disease-associated transcriptional programs. Inthe PFF model, REST restored mitochondrial and oxidative phosphorylation pathwayssuppressed by ¿-synuclein pathology. In the SNCA-OVX model, REST regulatedextracellular matrix organization, ion channel function, and vesicular trafficking, consistentwith broader roles in neuronal and glial homeostasis. In summary, REST acts as a contextanddose-dependent regulator of dopaminergic neuron resilience. When preciselymodulated, REST enhances mitochondrial integrity, supports protein clearance, andmitigates transcriptional stress responses. However, excessive REST expression leads todopaminergic dysfunction and motor deficits, highlighting REST as both a promisingtherapeutic target and a cautionary example for PD intervention strategies. 190 p.