Positive Lysosomal Modulation As a Unique Strategy to Treat Age-Related Protein Accumulation Diseases

UNCP Author/Contributor (non-UNCP co-authors, if there are any, appear on document)
Dr . Ben Bahr, William C. Friday Chair and Professor of Molecular Biology and Biochemistry (Creator)
The University of North Carolina at Pembroke (UNCP )
Web Site: http://www.uncp.edu/academics/library

Abstract: Lysosomes are involved in degrading and recycling cellular ingredients, and their disruption with age may contribute to amyloidogenesis, paired helical filaments (PHFs), and a-synuclein and mutant huntingtin aggregation. Lysosomal cathepsins are upregulated by accumulating proteins and more so by the modulator ZPhe-Ala-diazomethylketone(PADK). Such positive modulators of the lysosomal system have been studied in thewell-characterized hippocampal slice model of protein accumulation that exhibits the pathogenic cascade of tau aggregation, tubulin breakdown, microtubule destabilization, transport failure, and synaptic decline. Activecathepsins were upregulated by PADK; Rab proteins were modified as well, indicating enhanced trafficking, whereas lysosome-associated membrane protein and proteasome markers were unchanged. Lysosomal modulationreduced the pre-existing PHF deposits, restored tubulin structure and transport, and recovered synaptic components. Further proof-of-principle studies used Alzheimer disease mouse models. It was recently reported that systemic PADK administration caused dramatic increases in cathepsin B protein and activity levels, whereas neprilysin, insulin-degrading enzyme, a-secretase, and b-secretase were unaffected by PADK. In the transgenic models, PADK treatment resulted in clearance of intracellular amyloid beta (Ab) peptide and concomitant reduction of extracellular deposits. Production of the less pathogenic Ab1–38 peptide corresponded with decreased levels of Ab1–42, supporting the lysosome’s antiamyloidogenic role through intracellular truncation. Amelioration of synaptic and behavioral deficits also indicates a neuroprotective function of the lysosomalsystem, identifying lysosomal modulation as an avenue for disease-modifying therapies. From the in vitro and in vivo findings, unique lysosomal modulators represent a minimally invasive, pharmacologically controlledstrategy against protein accumulation disorders to enhance protein clearance, promote synaptic integrity, and slow the progression of dementia.

Additional Information

Rejuvenation Research Vol. 15, No. 2
Language: English
Date: 2012
Lysosomes, amyloidogenesis, paired helical filaments (PHFs), ZPhe-Ala-diazomethylketone (PADK), tau aggregation

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