My research aims to understand the role of proteases in the pathogenesis of degenerative diseases. Proteases play an important role in the cascade of events leading to cell death. Abnormal processing of proteins is an early event in several major degenerative disorders. We are particularly interested in characterizing the role of calpains (calcium-activated proteases) in Alzheimer’s disease (AD) and Parkinson’s disease (PD), and in understanding the interplay among the calpain, caspase, and cathepsin proteolytic systems in programmed cell death. I use both biochemical and immunochemical techniques to study proteases in postmortem human and animal tissues and in cell culture models. These studies also focus on the regulation of endogenous inhibitors that modulate the activities of the proteases. Based on our discovery of elevated lysosomal hydrolases in CSF of AD patients, we are developing a diagnostic test for Alzheimer’s disease. I am currently developing a sensitive assay for cathepsin D, a lysosomal enzyme especially elevated in AD brain and cerebrospinal fluid (CSF). The assay in conjunction with other available markers in CSF, such as tau protein and amyloid b peptide, will yield a profile with increased detection sensitivity.
Schwagerl AL, Mohan PS, Cataldo AM, Vonsattel JP, Kowall NW, Nixon RA. Elevated levels of the endosomal-lysosomal proteinase cathepsin D in cerebrospinal fluid in Alzheimer disease. J Neurochem. 1995 Jan;64(1):443-6.
Mohan PS, Nixon RA. Purification and properties of high molecular weight calpastatin from bovine brain. J Neurochem. 1995 Feb;64(2):859-66.
Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Näslund J, Mathews PM, Cataldo AM, Nixon RA. Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol. 2005 Oct 10;171(1):87-98.
Rao MV, Mohan PS, Peterhoff CM, Yang DS, Schmidt SD, Stavrides PH, Campbell J, Chen Y, Jiang Y, Paskevich PA, Cataldo AM, Haroutunian V, Nixon RA. Marked calpastatin (CAST) depletion in Alzheimer's disease accelerates cytoskeleton disruption and neurodegeneration: neuroprotection by CAST overexpression. J Neurosci. 2008 Nov 19;28(47):12241-54.
Kim S, Sato Y, Mohan PS, Peterhoff C, Pensalfini A, Rigoglioso A, Jiang Y, Nixon RA. Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer's disease. Mol Psychiatry. 2016 May;21(5):707-16.