TFEB Activation to Restore Lysosomal Biogenesis in Parkinson's Disease Dopaminergic Networks

Age-related decline in lysosomal function contributes to the accumulation of pathological protein aggregates in Parkinson’s disease, particularly alpha-synuclein oligomers and Lewy bodies that disrupt dopaminergic neurotransmission and cause progressive motor dysfunction. This hypothesis proposes that pharmacological or genetic activation of TFEB (Transcription Factor EB) can restore lysosomal biogenesis and autophagy flux specifically in dopaminergic neurons of the substantia nigra and striatal terminals. TFEB, a master regulator of the autophagy-lysosomal pathway, becomes sequestered in the cytoplasm during neurodegeneration, reducing its nuclear translocation and transcriptional activity in vulnerable dopaminergic populations. 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 specifically in dopaminergic circuits. This enhanced lysosomal capacity will improve clearance of aggregated alpha-synuclein from presynaptic terminals and dopaminergic cell bodies, preventing the formation of toxic oligomers and Lewy pathology. The intervention is expected to be most effective in early-stage Parkinson’s disease before extensive dopaminergic neuron loss occurs. Evidence will be gathered through longitudinal analysis of alpha-synuclein transgenic and MPTP-treated mouse models with TFEB activators, measuring dopaminergic neuron survival, striatal dopamine levels, and motor function using rotarod and cylinder tests. Biomarker studies will track lysosomal enzyme activity in cerebrospinal fluid and assess changes in brain alpha-synuclein burden using specialized PET tracers. This targeted approach addresses the fundamental cellular waste management deficits underlying Parkinson’s pathogenesis in dopaminergic networks.