The knockdown of the UCH-L1 in <i>Drosophila</i> can be used in studying the epidemiology of the disease as well as in drug screening for finding therapeutic targets for PD.
This suggests that pink1, atp13a2 and uchl1 expressions are regulated by inflammation, and this regulatory mechanism might be involved in the progress of PD.
Mechanistic studies in mice suggest the existence of multiple molecular contributors to the neuroprotective effects of NAPE-PLD deletion, including suppression of Rac1 activity and attenuated transcription of several genes (Cadps, Casp9, Egln1, Kcnj6, Spen, and Uchl1) implicated in dopamine neuron survival and/or Parkinson's disease.
Our findings, while drawn from a relatively small sample size, suggest that deregulation of APA may play a significant role in neurodegeneration by altering the expression of genes including UBR1 and OGDHL in AD, LONP1 in PD and UCHL1 in ALS.
We found connections between copper dyshomeostasis and the UCHL1/PARK5 pathway of Parkinson disease, which we validated with mitochondrial respiration and Drosophila genetics assays.
Finally, we summarize the effect of these genetic mutations and post-translational modifications on the association of UCHL1 and PD in terms of loss of cellular functions or gain of cellular toxicity.
Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a key neuronal deubiquitinating enzyme which is mutated in Parkinson disease (PD) and in childhood-onset neurodegenerative disorder with optic atrophy.
In conclusion, our meta-analysis suggests that UCHL1S18Y polymorphism is moderately associated with susceptibility to PD, and more studies are needed to confirm our conclusion.
We identified that elevated alpha-synuclein messenger RNA levels in SN DA neurons of human PD brains were positively correlated with corresponding elevated levels of mRNAs for functional compensation of progressive SN DA loss and for enhanced proteasomal (PARK5/UCHL1) and lysosomal (PARK9/ATPase13A2) function, possibly counteracting alpha-synuclein toxicity.
Thus, the current meta-analysis suggests no evidence for the association between the UCHL1S18Y polymorphism and PD risk in the Asian population, especially in subgroups of ethnicity and age at onset.
Furthermore, in the context of a-syn-induced pathology, modulation of UCH-L1 activity could serve as a therapeutic tool to enhance the autophagy pathway and induce clearance of the observed accumulated/aggregated a-syn species in the PD brain.
Overall, these data provide evidence for an antioxidant and neuroprotective effect of the S18Y variant of UCH-L1, but not of the WT protein, in the dopaminergic system, and may have implications for the pathogenesis of PD or related neurodegenerative conditions, in which oxidative stress might play a role.