DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Posted October 15, 2015
Clemens Scherzer, M.D., Harvard Medical School, Brigham and Women's Hospital

Clemens Scherzer, M.D. Parkinson's disease (PD) is a debilitating neurodegenerative disease. It is the second most common neurodegenerative condition after Alzheimer's disease and affects between one to two percent of individuals in their sixties, increasing to approximately four percent of individuals by age 80 (de Lau, et. al., 2006)i. The disease is characterized by the loss of dopaminergic cells in the substantia nigra with resulting movement dysfunction. Like other neurodegenerative diseases, the ability to identify people at high risk for developing the disorder is critical for early interventions, but identification of biomarkers prior to the development of the motor condition has been difficult.

Alpha-synuclein, a protein encoded by the SNCA gene, is known to accumulate in the brains of patients with PD, but the inability to measure this accumulation in living patients prevents its use as a biomarker of developing disease. The discovery of SNCA expressed in blood cells suggested a potential peripheral target (Nakai et al., 2007ii, Scherzer et al., 2008iii).

In a recent publicationiv funded by the NETPR (Neurotoxin Exposure Treatment Parkinson's Research) program, Dr. Clemens Scherzer and his collaborators show that levels of SNCA transcripts, measured from blood, are reduced in patients with PD. Dr. Scherzer and colleagues suggest a number of possible explanations for the surprising negative correlation. One hypothesis is that, in PD patients, alpha-synuclein protein levels accumulate and lead to a feedback repression of SNCA transcription.

The negative correlation of SNCA transcript levels with PD was replicated in three independent populations. Importantly, SNCA transcript levels were lower in patients even before they met current clinical diagnostic criteria. This result suggests the negative correlation of SNCA blood transcripts and PD prevalence may have value in predicting those likely to develop Parkinson's disease.

In addition to the hallmark motor symptoms in PD, many patients suffer from declining cognitive function. Given that cognitive decline is highly correlated with alpha-synuclein-positive Lewy body burden, Dr. Scherzer and colleagues were interested in knowing whether SNCA levels were related to cognitive functioning. Indeed, low SNCA transcript levels in patients with PD at the time of study enrollment predicted cognitive decline on tests assessing attention, memory, and language for up to five years after diagnosis. These results suggest that, if confirmed in further studies, SNCA transcript levels could serve as a risk indicator for PD as well as a means of identifying PD subpopulations, predicting progression of the disease and identifying therapeutic candidate interventions.

References:

i de Lau LM, Breteler MM; Breteler (June 2006). "Epidemiology of Parkinson's disease". Lancet Neurol. 5 (6): 525-35.

ii Nakai M, Fujita M, Waragai M, Sugama S, Wei J, Akatsu H, et al. Expression of alpha-synuclein, a presynaptic protein implicated in Parkinson's disease, in erythropoietic lineage. Biochem Biophys Res Commun 2007; 358: 104-10.

iii Scherzer CR, Grass JA, Liao Z, Zheng B, Pepivani I, Eklund AC, Ney PA, Ng J, McGoldrick M, Moellenhauer B, Bresnick EH, MG Schlossmacher. GATA transcription factors directly regulate the Parkinson's disease-linked gene alpha-synuclein. PNAS, 2008; 105: 10907-12.

iv Locascio J, Eberly S, Liao Z, Liu G, Hoesing A, Duong K, et al. Association between alpha-synuclein blood transcripts and early, neuroimaging-supported Parkinson's disease. Brain 2015; 138(Pt 9): 2659-71.

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