Parkinson's disease is the second most common neurodegenerative disease in humans.
It is slowly progressive, affecting many regions of the nervous system, including nigral dopaminergic neurons, and can eventually lead to dementia in addition to the well known motor symptoms. Alpha-synuclein (SNCA) is the protein responsible for Parkinson's disease. SNCA can convert to a toxic form and that toxic form propagates through the nervous system in a templated manner, dependent on endogenous production of SNCA. While the precise nature of the toxic form is not known, this mechanism indicates that SNCA is a prion. One potential therapeutic strategy would be reduction of endogenous SNCA production. Lowering the endogenous levels of SNCA would likely slow disease progression. However, the normal role of SNCA is not completely understood, so reducing SNCA levels might have unintended consequences. We have recently found that mice null for Snca(129S6-Scnatm1Nbm/Sncatm1Nbm) have a significantly shorter lifespan than WT mice, indicating that SNCA function is important in aging. This difference in lifespan appears at about 400 days and shortens overall lifespan by about 200 days. Conversion of SNCA to a toxic form in humans may prevent it from performing some needed role in aging, thus contributing to disease.
We performed a sensitized ENU mutagenesis screen using Snca null mice to better understand the protein's normal function. One sensitized mutation was identified after screening 125 pedigrees. This mutation occurred in the gene for ATP7A, a trans-Golgi copper transporter. Female mice carrying the X-linked mutation have a significantly higher rate of early death when they lack Snca than when the Atp7a mutation is on the Snca WT background. In humans, mutations in ATP7A cause Menkes disease. Linking SNCA and ATP7A genetically indicates that SNCA has a role in the trans-Golgi compartment. Immunofluorescence on both brain sections and on primary neurons derived from a) 129S6;B6J-Atp7am1Decn/Y Snca+/+, b) 129S6;B6J-Atp7am1Decn/Y Snca-/-, c) 129S6;B6J-Atp7a+/Y Snca+/+, d) 129S6;B6J-Atp7a+/Y Snca-/- mice indicates that SNCA is found in the trans-Golgi compartment, co-localizes with ATP7A, and seems to play a role in proper localization of ATP7A to axons. We are now examining brains of aged mice to determine aging affects SNCA and ATP7A subcellular localization, and whether lack of SNCA affects the trans-Golgi compartment during aging. Golgi fragmentation has been observed in Parkinson's disease, but whether this is due to SNCA toxicity or whether the loss of SNCA function plays a role is unknown.