Abstract
Recent studies have demonstrated that hyperphosphorylation of tau protein plays a role in neuronal toxicities of α-synuclein (ASYN) in neurodegenerative disease such as familial Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and Parkinson’s disease. Using a transgenic mouse model of Parkinson’s disease (PD) that expresses GFP-ASYN driven by the PDGF-β promoter, we investigated how accumulation of ASYN impacted axonal function. We found that retrograde axonal trafficking of brain-derived neurotrophic factor (BDNF) in DIV7 cultures of E18 cortical neurons was markedly impaired at the embryonic stage, even though hyperphosphorylation of tau was not detectable in these neurons at this stage. Interestingly, we found that overexpressed ASYN interacted with dynein and induced a significant increase in the activated levels of small Rab GTPases such as Rab5 and Rab7, both key regulators of endocytic processes. Furthermore, expression of ASYN resulted in neuronal atrophy in DIV7 cortical cultures of either from E18 transgenic mouse model or from rat E18 embryos that were transiently transfected with ASYN-GFP for 72 hrs. Our studies suggest that excessive ASYN likely alters endocytic pathways leading to axonal dysfunction in embryonic cortical neurons in PD mouse models.
Highlights
Parkinson’s disease (PD), one of the most common neurodegenerative diseases, is pathologically characterized by progressive loss of midbrain dopamine neurons and gradual development of intracellular proteinaceous aggregates termed Lewy bodies (LBs) and Lewy neurites (LNs)
E18 primary cortical neurons from transgenic mice and non-transgenic littermate controls were cultured in microfluidic chambers, by which axons are separated from the corresponding cell bodies[15, 18]
We have demonstrated that increased level of a role in neuronal toxicities of α-synuclein (ASYN) impeded retrograde axonal transport of brain-derived neurotrophic factor (BDNF) and inhibited BDNF-induced trophic signaling at the embryonic stage
Summary
Parkinson’s disease (PD), one of the most common neurodegenerative diseases, is pathologically characterized by progressive loss of midbrain dopamine neurons and gradual development of intracellular proteinaceous aggregates termed Lewy bodies (LBs) and Lewy neurites (LNs). Adeno-associated viral vectors (AAV)-mediated overexpression of ASYN in rodents resulted in neurodegeneration, resembling pathological changes in PD patients[8, 9]. These findings all point to an important role played by excessive accumulation of ASYN in the pathogenesis of PD. ASYN has a strong propensity to misfold and recent studies have suggested that ASYN may interact with tau to form deleterious hetero-oligomers for initiating and spreading of neurodegeneration in these diseases[14] These studies suggest that Tau is an important mediator in transmitting neuronal toxicities of ASYN
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