Study Identifies Two Molecules Driving the Loss of Specific Neurons in Parkinson’s Disease

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A research team at Colombia University led by Lars Brichta and Paul Greengard identified two proteins responsible for neuronal cell loss in Parkinson’s disease (PD). The study entitled “Identification of neurodegenerative factors using translatome–regulatory network analysis” appeared on 27 July, 2015 in the journal Nature Neurosciences.

PD is the second most common progressive neurodegenerative disease after Alzheimer’s disease. With an average onset age of 60 years, it affects around one million people in the United States, accounting for the 14th leading cause of death in the country.

It remains unclear why neurons in the substantia nigra pars compacta (SNpc), a midbrain region, are specifically affected in PD.  These neurons produce dopamine and its degeneration causes loss of motor control in PD patients. In this study, researchers used a new strategy to compare the molecular changes occurring in SNpc neurons with those occurring in neighboring brain region neurons, the ventral tegmental area (VTA). “Within a dying nerve cell, the levels of hundreds of proteins change,” said study author Paul Greengard in a press release. “Some of these shifts are consequences, others are causes. We set out to find which cause cell death among neurons.”

The team used genetically engineering mice to identify genes specifically translated into proteins within SNpc neurons of animals suffering from Parkinson’s-like degeneration. Using bioinformatics, researchers were able to identify the uspstream regulators of these genes. “Using a new combination of techniques,” Greengard added, “we identified two of these so-called master regulatory molecules — a discovery that offers an unexpected explanation as to why one population of neurons degenerates in Parkinson’s, while similar neighbors do not suffer from the same degree of degeneration.”

The authors identified SATB1 and ZDHHC2 as master regulatory molecules in SNpc neurons but not in VTA neurons as dysfunction of these two proteins only caused death of SNpc neurons. “Conventional gene activity profiling approaches would not have been able to identify SATB1 and ZDHHC2 as key protective factors because the levels of these proteins do not change. But even though they continue to be expressed within the neurons, it appears that their regulatory activity drops off and they no longer stimulate their target genes,” said study author Brichta. Importantly, these proteins were also shown to be relevant in PD patients.”The discovery of these two molecules’ role in Parkinson’s may assist in the development of treatments, because they are potential new targets for drugs,” added Greengard.

The researchers believe this same strategy may identify important players in other neurodegenerative diseases, including Alzheimer’s, spinal muscular atrophy, Huntington’s disease and amyotrophic lateral sclerosis.