The protein α-synuclein can misfold into a pathological form and then spread from cell to cell in the central nervous system. This occurs in everyone to some degree with age, but only some people experience a burden of α-synclein pathology large enough to lead to Parkinson's disease or other synucleinopathies. It is likely that everyone exhibits some loss of function due to α-synuclein, but as ever, it is hard to pin down exactly how much of each aspect of aging is due to any one specific mechanism. The only efficient way to obtain useful data is to fix that one specific problem and observe the outcome, which is what researchers did here in aged rats. A gene therapy produced intracellular antibodies that reduce α-synuclein levels, albeit perhaps not in the expected way, and the result is improved function in treated animals.
Abnormal accumulation of alpha-synuclein (αSyn) in axons and presynaptic terminals plays a critical role in αSyn-mediated dopaminergic neurodegeneration. A strong correlation between aging and elevated αSyn levels in the substantia nigra has been identified in both humans and non-human primates. This study aimed to investigate whether AAV-mediated NAC32 intrabody expression in the substantia nigra could ameliorate αSyn-associated dopaminergic dysfunction and improve age-related motor deficits in aged rats.
We first investigated the mechanism by which NAC32 reduces αSyn levels. Comparisons of αSyn burden, tyrosine hydroxylase (TH) expression, and locomotor activity were made between young and aged rats. In aged rats, we evaluated behavioral performance, dopaminergic markers, and synaptic markers following AAV1-NAC32 gene delivery into the substantia nigra. Our results showed that the NAC32-mediated αSyn reduction was not prevented by inhibition of proteasomal, lysosomal, or autophagic pathways and was associated with reduced αSyn mRNA levels.
Aged rats exhibited decreased locomotor activity, elevated αSyn levels, and reduced TH expression in the substantia nigra. NAC32 intrabody expression in the substantia nigra significantly reduced αSyn accumulation, restored TH expression, increased synaptic markers and striatal dopamine levels, and improved locomotor performance in aged rats. These effects occurred without detectable elevation of pro-inflammatory cytokine levels in bulk striatal tissue. Our findings suggest that AAV-mediated NAC32 intrabody expression in the substantia nigra may serve as a therapeutic strategy to mitigate αSyn-induced dopaminergic dysfunction and motor impairments associated with aging.
Link: https://doi.org/10.1038/s41598-025-34908-1
View the full article at FightAging
