UC San Diego

Parkinson’s Disease (PD) is the second most common neurodegenerative disease, which is characterized by the loss of dopaminergic neurons in the substantia nigra of the brain possibly due to the accumulation of α-synuclein (ASYN). Mutations or triplication of the ASYN gene (SNCA) contribute to synucleinopathies including PD, but studies have also noted that a significant portion of PD patients develop Alzheimer’s Disease (AD) like dementia. Therefore, we hypothesized that excessive accumulation of ASYN may also impact the trafficking and processing of the amyloid precursor protein (APP), initiating the pathogenesis of AD. To test our hypothesis, we used a transgenic mouse model of PD that over-expresses a green fluorescent protein fused human ASYN (GFP-hASYN) transgene. Our findings suggest that the over-expression of GFP-hASYN in mouse neurons i.e. PD neurons impaired axonal trafficking and processing of APP. Furthermore, APP carboxyl terminal fragment (APP CTF) levels were significantly higher in GFP-hASYN+ positive PD neurons than in GFP-hASYN- neurons, suggesting impairment in downstream processes. Interestingly, in ASYN knockout (SynKO) neurons, APP trafficking and processing was largely unaffected as compared to wildtype (WT) neurons’. Based on these observations, we speculate that selective impairment of trafficking and processing of APP by ASYN may give rise to toxic CTFs, which may contribute to blockages, leading to endosomal enlargement, axonal transport impairment and eventually neuronal atrophy. This study provides an important molecular mechanism by which excessive accumulation of ASYN could potentially be linked to cellular events that lead to AD pathogenesis in addition to its role in inducing neurotoxicity in PD pathology.