inhibition improved α-synuclein pathology, autophagy-lysosomal activity, metabolism, neuron preservation, and motor outcomes in Parkinson's disease mouse models.
Evidence
This preclinical study used MPTP-induced and AAV-A53T mouse models with TAL1 knockdown, autophagy-lysosomal gene assays, targeted metabolomics, locomotor testing, and substantia nigra pathology.
Caveat
The work is limited to experimental mouse models, so TAL1 targeting remains untested for efficacy or safety in human Parkinson's disease.
Simplified
Parkinson's disease (PD) progression involves dopaminergic neurodegeneration and pathological α-synuclein aggregation, processes linked to metabolic dysregulation and (ALP) impairment. Transaldolase1 () is a key enzyme of the pentose phosphate pathway. While elevated TAL1 protein levels have been observed in postmortem substantia nigra of PD patients, the enzyme's functional role in disease pathogenesis remains undefined. In this study, we explored the role of TAL1 in PD-related pathologies using MPTP-induced and AAV-A53T mouse models. We demonstrate that TAL1 upregulation is associated with dopaminergic neuron degeneration across both experimental models. TAL1 knockdown activated TFEB-mediated transcription of autophagy-lysosomal genes (Ctsb, Ctsd, Lamp1, Becn1, and Map1Lc3b). In addition, targeted metabolomics revealed that TAL1 knockdown modulates the energy pathways, especially in the TCA cycle, and glycolysis. The neuroprotective effects were mediated through AMPK/mTORC1 pathway activation, evidenced by increased AMP levels, p-AMPK/AMPK ratios, and downstream ALP enhancement. Importantly, TAL1 inhibition improved locomotor function in AAV-A53T mice and normalized stride length in footprint analysis. Pathological experiments confirmed reduced phospho-α-synuclein level and preserved the neuron loss in substantia nigra. Our findings highlight TAL1 as a regulator of autophagy-lysosomal function and energy metabolism in PD-related experimental models, where its inhibition restores the degradation of α-synuclein through coordinated activation of autophagy-lysosomal clearance and energetic reprogramming. These results suggest that targeting TAL1 may offer a potential therapeutic approach to mitigate PD-associated neuropathology.
Key numbers
811.5 µM
Expression Increase
IC50 for MPP toxicity in MN9D cells.
9 of 9
Motor Function Improvement
Mice in the + shTAL group improved in various motor tests.
Full Text
We can’t show the full text here under this license.
