Role of the Alzheimer's Disease Protein, Presenilin 1, in Lewy Body Diseases

Parkinson's disease (PD) and Alzheimer's disease overlap clinically and pathologically. While Alzheimer's patients often present extrapyramidal symptoms similar to those seen in PD, nearly 40 percent of PD patients develop dementia. On a molecular level, postmortem analysis of a growing number of PD patients reveals prevalent amyloid-beta plaque and neurofibrillary tangle pathology. Besides being the catalytic core of gamma-secretase, presenilin 1 (PSEN1) is a dynamic protein that traffics between numerous cellular compartments and participates in a number of cellular functions, including protein cleavage and processing, protein degradation, calcium regulation, cell-to-cell adhesion regulation, and autophagy.

Mutations found in PSEN1 are most commonly known to cause familial forms of Alzheimer's disease, frontotemporal dementia and Pick's disease. Interestingly, a growing number of PSEN1 mutations have been identified that cause a familial form of the synucleinopathy dementia with Lewy bodies, in which there is a marked accumulation of phosphorylated alpha-synuclein. The overlap in genetics and pathology in these neurodegenerative disorders suggests the convergence of common molecular pathways in these diseases.

Using genetic and molecular studies, Dr. McLean and her colleagues have strong evidence for a functional interaction of PSEN1 and alpha-synuclein. In collaboration with investigators at Massachusetts General Hospital, current projects aim to validate PSEN1 as a target for PD therapeutics based on its functional interaction with alpha-synuclein.