Despite significant investments of public and private resources in research on Alzheimer's disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS), Huntington’s disease (HD), and other neurodegenerative diseases, there are currently no neuroprotective therapies available for patients. The Center for Rare Neurological Diseases seeks to initiate and execute innovative therapeutic approaches that will address some of the previous obstacles in translational neurosciences.
Mechanism- and Genotype-based Therapies
In our recent work we found that Gaucher disease, a rare lysosomal storage disease that predominately affects children, is mechanistically linked to Parkinson’s disease (1,2). Specifically, we identified glucocereberosidase, an enzyme that causes Gaucher’s disease when mutated, as novel therapeutic target for Parkinson’s disease and related synucleinopathies. These discoveries provide a foundation for additional studies in the area of lysosomal diseases and neurodegeneration, including the examination of links between other lysosomal storage diseases (LSDs) and accumulations of Tau or Aβ that are associated with dementias such Alzheimer’s disease. We hypothesizes that accumulation of aggregation-prone proteins such α-synuclein, Tau, Aβ contribute to neurodegeneration in at least a subset of LSDs where it is known that these proteins accumulate. We propose to develop a novel approach to drug development by targeting specific enzymes and proteins linked to neurodegeneration in lysosomal storage diseases for therapeutic development in PD, AD and related neurodegenerative disorders.
Biomarkers and Early Interventions
The CRND will assess lysosomal enzymes and their respective substrates as possible biomarkers of disease progression in neurodegenerative diseases. The activities of lysosomal enzymes will be measured in peripheral and easily accessible compartments of patients with PD or AD, as well as in patients with the relevant lysosomal disorder. Using this approach we should be able to demonstrate specific activation of therapeutic targets in well-defined patient populations prior to disease onset. This approach, if successful, will allow for early, less expensive proof-of-concept studies and will lower the overall cost of clinical studies. We will closely collaborate with the Clinical Research center at our institution to design and organize these innovative clinical trials.
Following is a list of publications referenced in the development of our position and approach.
- Mazzulli, J.R., Sun, Y., Knight, A.L., McLean, P.J., Caldwell, G, Sidransky, E, Grabowski, G.A. and Krainc, D. Gaucher’s Disease Glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011 Jul 8;146(1):37-52. (Accompanied by the Perspective in Cell, Science Translational Medicine, and Editors’ Choice in Science) PMID: 21700325
- Shachar T, Lo Bianco C, Recchia A, Wiessner C, Raas-Rothschild A, Futerman AH. Lysosomal storage disorders and Parkinson's disease: Gaucher disease and beyond. Mov Disord. 2011 Aug 1;26(9):1593-604. PMID: 2161861