Abstract
Neutral sphingomyelinase smpd3 is most abundantly expressed in neurons of brain. The function of SMPD3 has remained elusive. Here, we report a pathogenetic nexus between absence of SMPD3 in the Golgi compartment (GC) of neurons of the smpd3-/- mouse brain, inhibition of Golgi vesicular protein transport and progressive cognitive impairment. Absence of SMPD3 activity in the Golgi sphingomyelin cycle impedes remodeling of the lipid bilayer, essential for budding and multivesicular body formation. Importantly, we show that inhibition of the Golgi vesicular protein transport causes accumulation of neurotoxic proteins APP, Aβ and phosphorylated Tau, dysproteostasis, unfolded protein response, and apoptosis, which ultimately manifests in progressive cognitive decline, similar to the pathognomonic signatures of familial and sporadic forms of Alzheimer´s disease. This discovery might contribute to the search for other primary pathogenic mechanisms, which link perturbed lipid bilayer structures and protein processing and transport in the neuronal Golgi compartment and neurodegeneration and cognitive deficits.
Highlights
Sphingomyelin (SM) is a major component of the lipid bilayer of subcellular membranes of mammalian central nervous system (CNS)
Neutral sphingomyelinase (SMPD3) expression in CNS is restricted to the Golgi complex of neurons
We unveiled a molecular link between SMPD3 deficiency in the SM cycle of the neuronal Golgi complex, impeded remodeling of the lipid bilayer of the Golgi membrane, essential for budding, vesicle formation and protein transport of amyloid precursor protein (APP), amyloid β (Aβ) and pTau, dysproteostasis, causing neurodegeneration and Alzheimer’s disease (AD)—like cognitive decline
Summary
Sphingomyelin (SM) is a major component of the lipid bilayer of subcellular membranes of mammalian central nervous system (CNS). Acid (SMPD1) and neutral sphingomyelinases (sphingomyelin phosphor-diesterases, SMases) (SMPD2 and SMPD3), hydrolyze SM and release ceramide and phosphoryl-choline. SMases differ in their enzymatic properties, regulation, tissue distribution, and subcellular localization. SM is degraded constitutively by acid SMase (SMPD1) in lysosomes[1,2,3,4]. Genetic defects in smpd[1] lead to the fatal human neurovisceral form of Niemann–Pick disease, type A, characterized by lysosomal SM storage in cells of the reticuloendothelial system and neurons. The SMPD1-deficient mouse mutant is a mimicry of NPD type A5,6. SMPD1 activity exceeds non-lysosomal neutral SMPD2 activity (nSMase1) in the endoplasmic
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