α-Synuclein Overexpression Induces Lysosomal Dysfunction and Autophagy Impairment in Human Neuroblastoma SH-SY5Y.
Ana Carolina NascimentoAdolfo G ErustesPatrícia ReckziegelClaudia BincolettoRodrigo P UreshinoGustavo José da Silva PereiraSoraya S SmailiPublished in: Neurochemical research (2020)
Although the etiology of Parkinson's disease (PD) is multifactorial, it has been linked to abnormal accumulation of α-synuclein (α-syn) in dopaminergic neurons, which could lead to dysfunctions on intracellular organelles, with potential neurodegeneration. Patients with familial early-onset PD frequently present mutation in the α-syn gene (SNCA), which encodes mutant α-syn forms, such as A30P and A53T, which potentially regulate Ca2+ unbalance. Here we investigated the effects of overexpression of wild-type α-syn (WT) and the mutant forms A30P and A53T, on modulation of lysosomal Ca2+ stores and further autophagy activation. We found that in α-syn-overexpressing cells, there was a decrease in Ca2+ released from endoplasmic reticulum (ER) which is related to the increase in lysosomal Ca2+ release, coupled to lysosomal pH alkalization. Interestingly, α-syn-overexpressing cells showed lower LAMP1 levels, and a disruption of lysosomal morphology and distribution, affecting autophagy. Interestingly, all these effects were more evident with A53T mutant isoform when compared to A30P and WT α-syn types, indicating that the pathogenic phenotype for PD is potentially related to impairment of α-syn degradation. Taken together, these events directly impact PD-related dysfunctions, being considered possible molecular targets for neuroprotection.
Keyphrases
- early onset
- wild type
- induced apoptosis
- endoplasmic reticulum stress
- endoplasmic reticulum
- cell death
- oxidative stress
- signaling pathway
- cell cycle arrest
- cell proliferation
- late onset
- endothelial cells
- protein kinase
- spinal cord
- genome wide
- gene expression
- spinal cord injury
- dna methylation
- reactive oxygen species
- copy number
- climate change
- induced pluripotent stem cells