Abstract
Previously, we demonstrated increased calcium levels and synaptic vesicle densities in the motor axon terminals (MATs) of sporadic amyotrophic lateral sclerosis (ALS) patients. Such alterations could be conferred to mice with an intraperitoneal injection of sera from these patients or with purified immunoglobulin G. Later, we confirmed the presence of similar alterations in the superoxide dismutase 1 G93A transgenic mouse strain model of familial ALS. These consistent observations suggested that calcium plays a central role in the pathomechanism of ALS. This may be further reinforced by completing a similar analytical study of the MATs of ALS patients with identified mutations. However, due to the low yield of muscle biopsy samples containing MATs, and the low incidence of ALS patients with the identified mutations, these examinations are not technically feasible. Alternatively, a passive transfer of sera from ALS patients with known mutations was used, and the MATs of the inoculated mice were tested for alterations in their calcium homeostasis and synaptic activity. Patients with 11 different ALS-related mutations participated in the study. Intraperitoneal injection of sera from these patients on two consecutive days resulted in elevated intracellular calcium levels and increased vesicle densities in the MATs of mice, which is comparable to the effect of the passive transfer from sporadic patients. Our results support the idea that the pathomechanism underlying the identical manifestation of the disease with or without identified mutations is based on a common final pathway, in which increasing calcium levels play a central role.
Highlights
Amyotrophic lateral sclerosis (ALS) is one of the most common motor neuron diseases, which, according to the historical principles of neurology, primarily affects the upper and lower motor neurons [1]
In our pioneering study with electron microscopic analyses, we described an elevated calcium level accompanied by an increased number of synaptic vesicles in the motor axon terminals obtained from sporadic ALS patients [26]
Nowadays it is widely accepted that increased calcium levels are a key factor in acute injuries [10,33] and in the pathobiology of neurodegenerative diseases [19,21,34,35,36,37]
Summary
Amyotrophic lateral sclerosis (ALS) is one of the most common motor neuron diseases, which, according to the historical principles of neurology, primarily affects the upper and lower motor neurons [1]. In our pioneering study with electron microscopic analyses, we described an elevated calcium level accompanied by an increased number of synaptic vesicles in the motor axon terminals obtained from sporadic ALS patients [26] While these results documented for the first time the perturbed calcium homeostasis in degenerating human nerve cells, the applied sampling was not uniform, since it was restricted to a subpopulation of ALS patients with sporadic classifications and no identified mutations. Based on our human muscle biopsy study, motor axon terminals could be localized in only 10% of the 71 patients who underwent a routine biopsy of the biceps muscles in a period of 9 months [26] In view of these numbers, and because of the low incidence of patients with familial history or identified mutations, similar examinations are not feasible, since according to the current epidemiological data [27], the worldwide prevalence of ALS is 4–8 persons/100,000 inhabitants. TwTwelevleveAALLSSppaattiieents wwiitthhidideenntitfiifiededmmutuataiotniosn, ws,itwhiothr worithwoiutht foaumt iflaymhislytorhyis(towroyp(atwtieonptsahtiaednts hando nfaomfialymhiliystohriystoorryknoorwknnmowutnatmiountsa)twioenrse)inwtreordeuincetrdotdouthceedsttuodtyh. eSesrtaupdrye.pSaerread pfrroempatrheedpfartoiemntsthe pawtieernetsinwtrearpeeirnittroanpeearliltyoninejaelclytedinjiencttoedminicteo fmorice fdoray2sdwayitshwditahilydaiinlyjeicntijoenctsi,onthse, nthethnethmeomtoortoarxaoxnon tetremrminianlaslws wereereanaanlaylzyezdedeleelcetcrtornonmmicircoroscsocoppiciacalllylytotoddeeteterrmminineeththeeccaalclciuiummccoonntteennttaannddtthheennuummbbeerr of syonfaspytnicavpetiscicvleess.icTlehse. oTbhseerovbesderivnecdreianscereinascealicniucmalclieuvmelsleavnedlsthanedelethveateeldevnautemdbneur mofbseyrnoafpstiycnvaepstiiccles invtehseiclaexsoinn ttehremaixnoanlst,etromgientahles,r twogitehthtehrewpirthevtihoeusproebvsioeurvsaotibosnersvoaftioelnesvoafteedlecvaaltceidumcalicniutmheingetnheetic mgoedneeltoicf mfamodielilaol fAfLaSmailniadl tAhLe Spaasnsdivtehterapnassfseivr emtoradneslfoefr smpoodraedl iocfAspLoSr,apdriocvAidLeSa, dpdroitvioidnealaddadtiatifoonratlhe codnacteapftotrhtahteecleovnacteepdt tchaalctieulmevlaetvedelscaplclaiuyma cleevnetlrsalprlaoyleaincetnhteraplartohloeminecthheanpiastmhoomf eAcLhaSn. iTshmisocfoAmLmS.on deTfinhnoiasml csiotnamagtmeo.romn dayencoomntirniabtuotremtoaythceonidtreinbtuictealtocltihneiciadlemntaicnailfecslitnaitcioanl mofanthifeesdtiasteioanseoifnthitesdfiinseaalssetaingei.ts
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