Molecular identification of ALDH1A1 and SIRT2 in the astrocytic putrescine-to-GABA metabolic pathway

Abstract

GABA (gamma-aminobutyric acid) is the primary inhibitory neurotransmitter in the CNS. In astrocytes, GABA is synthesized by degradation of putrescine by monoamine oxidase B (MAO-B), a process which is known to mediate tonic inhibition of neuronal excitability. This astrocytic tonic GABA and related enzymes are also reported to be involved in memory impairment in Alzheimers Disease, and therefore are potential therapeutic targets to rescue memory in AD patients. However, the enzymes downstream of MAO-B in this pathway have not been elucidated yet. To fill this gap in knowledge, we performed transcriptomic and literature database analysis and identified Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) and a histone deacetylase enzyme Sirtuin2 (SIRT2) as plausible candidate enzymes in primary cultured astrocytes. Immunostaining, metabolite analyses, and sniffer patch clamp performed in the presence or absence of suitable inhibitors, or with genetic ablation of the candidate enzymes recapitulated their participation in GABA production. We propose ALDH1A1 and SIRT2 as potential therapeutic targets against Alzheimers Disease.

Putrescine acetyltransferase (PAT/SAT1) dependent GABA synthesis in astrocytes

“…N 1acetylputrescine converted from putrescine is oxidized by MAO-B and becomes N 1 -acetyl-gaminobutyraldehyde. N 1 -acetyl-g-aminobutyraldehyde is dehydrogenated to N 1 -acetyl-GABA by ALDH1A1 and further deacetylated to GABA by sirtuin 2 (Bhalla et al, 2023). Every step except the first step has been defined in the astrocytic MAO-B-dependent GABA synthesis.…”