Decreasing levels of a-synuclein (SYN) is a promising therapeutic strategy for PD, but the safety of lowering SYN has not been established. Although the normal functions of SYN are unclear, SYN interacts with mitochondria, and too much or too little SYN may adversely affect mitochondria. Our goal is to determine if therapeutic reduction of SYN levels compromises the function of mitochondria.
We will use pre-clinical models in which SYN has been deleted to determine if loss of SYN compromises mitochondrial function in neurons. We will first study the impact on the overall mitochondrial function of individual neurons. We will then use recently developed assays to determine the impact of loss of SYN on energy levels at the nerve terminal where SYN concentrates. We will then determine the effects of SYN loss on overall metabolic function, looking both in areas that degenerate in PD and at the organism level.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Overwhelming evidence indicates that mitochondrial function is compromised in PD. Therefore, any therapeutic strategy aimed at modifying SYN levels will be made on a background of damaged mitochondria, and additional damage to these mitochondria would be likely to exacerbate the disease. The finding that increased a-SYN disrupts important mitochondrial functions, including their ability to move, divide, and produce energy, makes it all the more imperative to understand if and how decreasing SYN levels influences the function of this critical organelle.
We expect to gain insight into if and how SYN normally affects mitochondrial function. Negative results would suggest that SYN can be lowered therapeutically without compromising (and perhaps even improving) mitochondrial function. Conversely, if loss of SYN is detrimental to mitochondrial function, it will be important to determine the extent to which SYN can be safely lowered in PD before adverse events develop.
We found no adverse effects of lowering alpha-synuclein on the mitochondrial function of neurons. Neurons lacking alpha-synuclein were still able to produce energy and maintain normal energy levels. In addition, decreasing alpha-synuclein had no effect on the number or distribution of mitochondria, even in regions that degenerate in PD. Energy production was also preserved at the organism level. These findings suggest that alpha-synuclein normally has little direct impact on mitochondria, and/or that other proteins can compensate when alpha-synuclein is lost. Our data from preclinical models thus suggests that therapeutic reduction of alpha-synuclein levels will be safe from a mitochondrial perspective.