Reserpine modulates neurotransmitter release to extend lifespan and alleviate age-dependent Aβ proteotoxicity in Caenorhabditis elegans.
Aging is a debilitating process often associated with chronic diseases such as diabetes, cardiovascular and neurodegenerative diseases like Alzheimer's disease (AD). AD occurs at a very high incidence posing a huge burden to the society. Model organisms such as C. elegans become essential to understand aging or lifespan extension - the etiology, molecular mechanism and identification of new drugs against age associated diseases. The AD model, manifesting Aβ proteotoxicity, in C. elegans is well established and has provided valuable insights. Earlier, we have reported that Reserpine, an FDA-approved antihypertensive drug, increases C. elegans lifespan with a high quality of life and ameliorates Aβ toxicity in C. elegans. But reserpine does not seem to act through the known lifespan extension pathways or inhibition of its known target, vesicular monoamine transporter, VMAT. Reserpine's mode of action and the pathways it activates are not known. Here, we have evaluated the presynaptic neurotransmitter(s) release pathway and identified acetylcholine (ACh) as the crucial player for reserpine's action. The corroborating evidences are: i) lack of lifespan extension in the ACh loss of function (hypomorphic) - synthesis (cha-1) and transport (unc-17) mutants; ii) mitigation of chronic aldicarb effect; iii) lifespan extension in dopamine (cat-2) and dopamine and serotonin (bas-1) biosynthetic mutants; iv) no rescue from exogenous serotonin induced paralysis in the AD model worms; upon reserpine treatment. Thus, modulation of acetylcholine is essential for reserpine's action.
Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, India.
Kopal
K
Saharia
Upasna
U
Arya
Ranjeet
R
Kumar
Rashmi
R
Sahu
Chinmaya Kumar
CK
Das
Kuldeep
K
Gupta
Hemalata
H
Dwivedi
Jamuna R
JR
Subramaniam
D000109:Acetylcholine / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000448:Aldicarb; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D008136:Longevity / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D012110:Reserpine / Q000494:pharmacology*; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000959:Antihypertensive Agents; D002800:Cholinesterase Inhibitors; D018377:Neurotransmitter Agents; D050493:Vesicular Monoamine Transport Proteins; D012110:Reserpine; D000448:Aldicarb; D000109:Acetylcholine