TFEB Activation to Restore Lysosomal Function in Parkinson's Disease Alpha-Synuclein Clearance

Parkinson’s disease is characterized by the accumulation of misfolded alpha-synuclein protein aggregates (Lewy bodies) in dopaminergic neurons of the substantia nigra, leading to progressive motor dysfunction and neuronal death. This hypothesis proposes that pharmacological or genetic activation of TFEB (Transcription Factor EB) can restore lysosomal biogenesis and enhance alpha-synuclein clearance specifically in Parkinson’s disease-affected brain regions. TFEB dysfunction and impaired autophagy-lysosomal pathway activity are hallmarks of Parkinson’s pathogenesis, where cytoplasmic sequestration of TFEB reduces lysosomal capacity. By enhancing TFEB nuclear localization through mTORC1 inhibition, trehalose treatment, or direct TFEB overexpression, we can upregulate expression of lysosomal genes including LAMP1, cathepsins, and V-ATPase subunits. This enhanced lysosomal capacity will improve clearance of aggregated alpha-synuclein oligomers and fibrils from dopaminergic neurons, preventing their spread to interconnected brain regions via prion-like transmission. The intervention targets the specific vulnerability of dopaminergic neurons to alpha-synuclein toxicity and lysosomal dysfunction. Evidence will be gathered through longitudinal analysis of A53T alpha-synuclein transgenic and MPTP-induced Parkinson’s mouse models treated with TFEB activators, measuring dopaminergic neuron survival, striatal dopamine levels, and motor behavior. Biomarker studies will track lysosomal enzyme activity in cerebrospinal fluid and assess changes in alpha-synuclein burden using specialized PET tracers. This approach addresses the fundamental protein clearance deficits underlying Parkinson’s neurodegeneration by targeting the primary pathological protein species.