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Considering the substantial impact of genetic therapies for spinal muscular atrophy (SMA), longitudinal follow-up of patients undergoing treatment is crucial to effectively monitor treatment response. While functional rating scales are commonly used as primary outcome measures, they may not fully capture all the therapeutic benefits. To address this limitation, the phosphorylated neurofilament heavy chain (pNFH) protein has emerged as a promising biomarker for evaluating treatment response. pNF-H is a neuron- specific filament that exhibits increased levels in the cerebrospinal fluid (CSF) and plasma in the presence of neuronal degeneration. Our study includes individuals treated with Nusinersen (CSF and plasma samples) and Risdiplam (plasma), as well as age- and sex-matched control subjects (CSF and plasma). By examining the dynamics of pNF-H levels in these groups, we sought to identify significant differences indicative of treatment response. Before treatment, SMA individuals typically exhibit higher levels of pNF-H compared to non-SMA individuals. Elevated levels of pNF-H are associated with more severe clinical manifestations of the disease. During Nusinersen treatment, a notable decline in pNF-H levels during the first 2 months can be observed. Current findings suggest that genetic therapies have a notable impact on reducing pNF-H levels over time. By examining the changes in pNF-H levels, our study offers valuable insights into the underlying biochemical alterations associated with these therapies. Furthermore, it supports the use of pNF-H as a complementary measure to functional rating scales and as a potential biomarker for evaluating treatment effectiveness and monitoring disease progression in SMA.

Background: Recent literature data highlights metabolic changes in amyotrophic lateral sclerosis (ALS). To explore possible early metabolic changes, we aimed to analyse the fatty acids (FA) composition of erythrocytes in newly diagnosed als patients and to see whether fatty acid levels correlate with the ALSFRS-R score or disease duration. Methods: The severity of motor function involvement was assessed by the ALSFRS-R scale at the initial evaluation. The fatty acid profile of erythrocyte membranes was analysed by gas-liquid chromatography. The study comprised 26 clinically diagnosed als patients, with mean ALSFRS-R 38±8. The control group included 26 healthy volunteers. Results: Significantly higher levels of palmitic acid and total saturated FAs were detected in als patients. In als patients, total monounsaturated FA, palmitoleic, vaccenic, and oleic acid were also significantly increased. The levels of eicosapentaenoic acid, docosapentaenoic acid, total polyunsaturated FA (PUFA) and n-6 PUFA were significantly lower in als patients. Additionally, a-linolenic acid, the precursor of the n-3 PUFA family, was not detected in als patients. We found no significant correlation between the ALSFRS-R score and the abundance of individual FAs analysed. A moderate negative correlation was found between disease duration and DHA level, and a positive correlation was detected with MUFA. Conclusion: Experimental evidence presented may contribute to shaping a beneficial nutritional intervention.

Radicava™ (Edaravone) was approved the Food and Drug Administration (FDA) as a new treatment for amyotrophic lateral sclerosis (ALS). Edaravone is a synthetic antioxidant that specifically targets oxidative damage interacting with lipid radicals in the cell. In ALS disease the multiple cell types are involved in devastating loss of motor neurons. Mutations and biochemical changes in various cell types jointly contribute to motor neuron death, disease onset, and disease progression. The overall mechanism of neurodegeneration in ALS is still not completely understood. Dying motor neurons have been reported to exhibit features of apoptosis. However, non-apoptotic features of dying motor neurons have also been reported such as ferroptosis. The role of Edaravone in the prevention of ferroptosis in parallel with other therapeutic approaches to ALS therapy is discussed.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disorder that may lead to functional impairment, including gait abnormalities. Our aim was to analyze gait characteristics in patients with CIDP compared to healthy controls (HC). Moreover, we sought to determine changes of gait parameters after six-month follow-up period. Twenty-four patients with CIDP and 24 HCs performed basic walking task, dual-motor task, dual-mental task, and combined task using the same GAITRite system. Lower limb MRC-SS and lower limb INCAT disability score were assessed. Fourteen patients were retested after six months. Majority of gait parameters showed significant differences in all experimental conditions when compared between CIDP and HCs. The most consistent findings in CIDP were shorter stride length (SL), prolonged cycle time (CT) and double support time (DS), as well as increased variation of SL and of swing time (ST) (p lt 0.05). During follow-up, INCAT improved in nine (64.3%) of 14 patients and MRC-SS improved in eight (57.1%) patients. Six-month changes of CT and its variation during combined task significantly differentiated patients with improved vs. non-improved INCAT (p lt 0.05). In conclusion, patients with CIDP had slower gait with prolonged DS and with shorter SL compared to HCs. Increased variation of SL and of ST in CIDP may suggest a potential risk for instability and falls. Shorter CT duration and less CT variation during time correlated well with improvement in disability.

U evaluaciji kognitivnih promena karakterističnih za Alzheimer-ovu bolest (AB) i blagi kognitivni poremećaj (BKP) u odnosu na normalno starenje, neuropsihološko ispitivanje danas ima primat u odnosu na sve ostale metode. Cilj rada bio je da se utvrdi dijagnostička vrednost odabranih neuropsiholoških testova u razlikovanju osoba sa demencijom u AB i BKP međusobno kao i u odnosu na normalno starenje, odrede granične vrednosti korisne u kliničkom radu i optimalna baterija testova koja će omogućiti najtačniju klasifikaciju. METOD: Istraživanje je sprovedeno u Centru za poremećaje pamćenja i demencije Klinike za neurologiju, Kliničkog Centra Srbije, u periodu od marta 2010. do septembra 2015. godine, gde je, iz primarne kohorte koju čini 2198 ispitanika koji se prate neurološki i neuropsihološki od septembra 2008. godine, regrutovano 444 ispitanika, starijih od 60 godina, koji su u razmaku od godinu dana u dva navrata neuropsihološki testirani (183 pacijenta sa dijagnozom AB, 132 sa dijagnozom BKP i 129 zdravih ispitanika koji su činili kontrolnu grupu). Baterija neuropsiholoških testova obuhvatila je sledeće testove: 1) testove globalnog kognitivnog funkcionisanja: Mini Mental State Examination (MMSE), Clock Drawing Test (CDT), Addenbrooke's Cognitivne examination – revised (ACE-R), Mattis-ovu skalu za procenu demencije, 2) testove verbalnog epizodičkog pamćenja: The Free and Cued Selective Reminding Test - Grober - Buschke (FCSRT-GB), Rey Auditory Verbal Learning Task (RAVLT), 3) testove verbalne fluentnosti – Fonemska i kategorijalna fluentnost (FF i KF), 4) test konfrontacionog imenovanja: Boston Naming Test (BNT). REZULTATI: Test sa najvećom dijagnostičkom preciznošću izdvaja se ACE - R, sa optimalnom cut off vrednošću za razlikovanje kognicije zdravih od osoba sa BKP 82,5 (Se 0.800, Sp 0.907) i u razlikovanju kognicije osoba sa BKP u odnosu na umerenu AB cut off vrednošću 70,5 (Se 0.852, Sp 0.856). Od domenski orijentisanih testova izdavaja se domen verbalnog epizo, In the evaluation of cognitive changes characteristic of Alzheimer's disease (AD) and mild cognitive impairment (MCI) in relation to normal aging, neuropsychological testing has primacy today comparing to other methods. The aims of this study was to determine the diagnostic value of selected neuropsychological tests in distinguishing dementia in AD and MCI from each other as well as in relation to normal aging, determining the cut off values useful in clinical work and the optimal battery of tests that will enable the most accurate classification. METHOD: The research was conducted at the Center for memory disorders and dementia at Neurology Clinic of the Clinical Center of Serbia in the period from March 2010. to September 2015. From a primary cohort of the Center, comprised of 2198 subjects and monitored neurologically and neuropsychologically since September 2008., 444 subjects over 60 years of age were recruited. All subject were neuropsychologically tested and retested after one year (183 patients diagnosed with AD, 132 with MCI diagnosis and 129 healthy subjects who constituted a control group). The battery of neuropsychological tests included the following tests: 1) global cognitive function tests: Mini Mental State Examination (MMSE), Clock Drawing Test (CDT), Addenbrooke's Cognitive Examination - Revised (ACE-R), Mattis Scale for Dementia Assessment, 2) verbal episodic memory: The Free and Cued Selective Reminding Test - Grober - Buschke (FCSRT-GB), Rey Auditory Verbal Learning Task (RAVLT), 3) Verbal fluency: Phonemic and category fluency tests (FF and CF), 4) Confrontation naming: Boston Naming Test (BNT). RESULTS: A test with the highest diagnostic precision we obtained ACE - R, and determined optimal cut off value 82.5 (Se 0.800, Sp 0.907) to differentiate between healthy control and persons with MCI, and cut off value 70.5 (Se 0.852, Sp 0.856) to differentiate between individuals with MCI and patients with moderate AD. From domain-oriented tests, a dom

Amiotrofična lateralna skleroza (ALS) nastaje usled primarnog oštećenja motornih neurona na nivou kore velikog mozga, jedara moždanog stabla i prednjih rogova kičmene moždine. Oko 90% ALS pacijenata čini tzv. sporadičnu ALS (SALS), dok 5-10% pacijenta ima genetsku ili familijarnu osnovu bolesti (FALS). Do sada je opisano više od 20 gena povezanih sa ALS. Nisu poznate epidemiološke i kliničke karakteristike pojedinih formi FALS u Srbiji. U svetu nedostaju podaci o zahvaćenosti centralnog nervnog sistema (CNS) u sklopu FALS. Ciljevi ovog istraživanja su bili: molekularno-genetsko ispitivanje pacijenata sa ALS na prostoru Srbije; određivanje tipičnih kliničkih znakova u subpopulaciji pacijenata sa FALS; ispitivanje korelacija kliničkih i genetskih karakteristika, uključujući poređenje nalaza neuropsihološkog testiranja i morfoloških specifičnosti mozga i kičmene moždine analiziranih pomoću savremenih metoda magnetne rezonancije (MR). Metod: U ovo ispitivanje uključen je 241 pacijent iz hospitalnog registra Klinike za neurologiju Kliničkog centra Srbije. Pacijenti su testirani na sledeće mutacije: SOD1 (svih 5 egzona), TDP 43 (egzon 6), FUS (egzoni 14 i 15), c9orf72 i ANG. Genetska grupa od 37 ispitanika poređena je klinički sa 32 SALS pacijenta bez verifikovane mutacije. Neuropsihološko testiranje je sprovedeno kod 22 SOD1 pozitivna ispitanika, 5 SOD1 negativnih ispitanika pozitivnih na druge ALS gene i 82 zdrave kontrole. Primenjivani su testovi za kognitivni skrining, procenu opšteg intelektualnog nivoa, pažnje, pamćenja, vizuospacijalnih i konstrukcionih, egzekutivnih i jezičkih funkcija. Od 69 pacijenta sa ALS, MR pregledom mozga i vratnog dela kičmene moždine na aparatu od 1,5T je obuhvaćena grupa od 23 genetski determinisanih pacijenata i 11 iz grupe SALS. Kontrolna grupa bila je sastavljena od 34 uparena zdrava ispitanika. Analizirana je debljina korteksa, mikrostruktura puteva bele mase, funkcionalna povezanost delova mozga u stanju mirovanja, kao i analiza str, Amyotrophic lateral sclerosis (ALS) is caused by damage of motor neurons in bran cortex, brainstem and the spinal cord. About 90% of ALS patients have sporadic disease form (SALS), while 5-10% of patients have a genetic or familial disease (FALS). So far, more than 20 genes have been associated with ALS. The epidemiological and clinical characteristics of certain forms of FALS in Serbia are not known. Furthermore, there is a lack of data on central nervous system (CNS) involvement in FALS worldwide, both in terms of neuroimaging and cognitive testing. The objectives of this research were: molecular-genetic testing of ALS patients in Serbia; determination of typical clinical signs in subpopulation of patients with FALS; correlations of clinical and genetic characteristics, including neuropsychological testing and morphological specificities of the brain and spinal cord analyzed using modern magnetic resonance imaging (MRI) methods. Method: This study included 241 patients from the Neurology Clinic, Clinical Center of Serbia. Patients were tested for the following mutations: SOD1 (all 5 exons), TDP 43 (exon 6), FUS (exon 14 and 15), c9orf72 and ANG. A genetic group of 37 subjects was compared clinically with 32 SALS patients without a verified mutation. Neuropsychological testing was performed in 22 SOD1 positive subjects, 5 SOD1 negative subjects positive for other ALS genes and 82 healthy controls (HCs). Cognitive screening, as well as tests of general intellectual level, attention, memory, visuospacial, executive and linguistic functions were applied. Of the 69 patients with ALS, MRI examination of the brain and cervical spinal cord on the 1.5T equipment were conducted on 23 genetically determined patients and 11 SALS subjects. The control group was composed of 34 subjects macthed for gender and age. Cortical thickness analysis, white matter microstructural assessment, functional MRI at resting state, and the analysis of the spinal cord were made. Results: A total

Oštećenje perifernih nerava kod osoba obolelih od karcinoma pluća uobičajeno se povezuje sa paraneoplastičnim neuropatijama ili sa neurotoksičnim dejstvom hemioterapije. Paraneoplastične neuropatije predstavljaju deo paraneoplastičnih neuroloških sindroma, koji se retko sreću, kod manje od 1% svih pacijenata sa malignitetom. Kliničke i elektrofiziološke karakteristike paraneoplastičnih neuropatija su uglavnom povezane sa onkoneuronalnim antitelima. Paraneoplastične neuropatije ponekad ozbiljno komplikuju klinički tok maligne bolesti, izazivajući onesposobljenost pacijenata, što značajno narušava kvalitet života. Neuropatski bol je čest simptom perifernih neuropatija i u značajnoj meri negativno utiče na svakodnevni socijalni i porodični život pacijenata. Stav Evropskog Udruženja Neurologa (European Federation of Neurological Society (EFNS)) je da je problem adekvatnog lečenja bola i dalje aktuelan. Cilj rada: Cilj našeg rada je da ispta efekte Transkutane Električne Nervne Stimulacije (TENS) na intezitet neuropatskog bola kod pacijenata obolelih od karcinoma pluća, da sagleda da li smanjenje bola utiče na promene u kvalitetu života pacijenata, da utvrdi učestalost i prediktore nastanka pareneoplastičnih neuropatija i neuropatija indukovanih cisplatinskom hemioterapijom, u našoj sredini. Metod: Istraživanje koje je sprovedeno po tipu panel studije obuhvatilo je 106 pacijenata obolelih od karcinomom pluća lečenih u Kliničkom centru Srbije u periodu između 2013. i 2018. god. Istraživanje je sprovedeno u tri faze. U prvoj fazi sprovedena je prospektivna kohortna studija, u drugom delu praćena je subkohorta bolesnika lečenih cisplatinskom hemioterapijom, a u trećoj fazi praćeni su ispitanici sa klinički i elektrofiziološki dijagnostikovanom neuropatijom pre i posle terapije TENS-om. Iz istraživanja su isključeni svi pacijenti koji boluju od poznatih uzroka perifernih neuropatija. Uključeni pacijenti su inicijalno i nakon 4 meseca hemioterapije podvrgnuti detaljnoj neurol, Peripheral nerve damage in people with lung cancer is commonly associated with paraneoplastic neuropathy or with neurotoxic chemotherapy. Paraneoplastic neuropathies are a part of paraneoplastic neurological syndromes which are rarely found in less than 1% of all patients with malignancy. Clinical and electrophysiological characteristics of paraneoplastic neuropathies are mainly associated with onconeuronal antibodies. Sometimes they seriously complicate the clinical course of malignancy and frequently cause major disability and limitation in patients´ daily activities which significantly impair/impairs quality of life. Neuropathic pain is a common symptom of peripheral neuropathy and significantly affects daily social and family life of patients. European Federation of Neurological Society (EFNS) is of the opinion that the problem of adequate pain management remains relevant. Objective. The aim of our work is to determine Transcutaneous Electrical Nerv Stimulation (TENS) effects on intensity of neuropathic pain in paitents with lung cancer and to see if pain reduction affects changes in their quality of life as well as to establish frequency and predictors of emergence of both parenoplastic neuropathy and neuropathy induced by cisplatinoma in our community. Accordingly, we wanted to establish the incidence of parenoplastic neuropathy and neuropathy induced by cisplatinoma chemotherapy in our community. Method. We performed a prospective cohort study, on the basis of the panel study, with 106 lung cancer patients from 2013 to 2018, at the Clinical Center of Serbia. The research was carried out in three phases. The first phase refers to performing prospective cohort study.In the second part, the subcohort of patients treated with cisplatinoma chemotherapy was followed while in the third stage were followed the patients with clinically and electrophysiologicly diagnostified neuropathy, before and after applying TENS therapy. The study excluded all patients with well-k

Spinalna mišićna atrofija (SMA) i amiotrofična lateralna skleroza (ALS) su bolesti motoneurona. SMA je najčešći monogenski uzročnik smrtnosti dece, dok je ALS adultna, neizlečiva bolest sa vrlo progresivnim tokom. SMA je uzrokovana homozigotnim odsustvom gena SMN1 u telomernom delu segmentalne duplikacije 5q13.2, dok se u njenom centromernom delu nalazi gotovo istovetan gen SMN2 koji daje ~10% funkcionalnog proteina SMN. Klinička prezentacija SMA je izuzetno varijabilna i kreće se od najtežeg oblika kod novorođenčadi (tip I) do blagog oblika sa adultnim početkom (tip IV). Homogenost uzročne mutacije i izražena fenotipska heterogenost ukazuju na postojanje genetičkih, epigenetičkih i sredinskih faktora koji modifikuju fenotip SMA. Visoka stopa nejednakih hromozomskih rearanžmana u segmentalnoj duplikaciji 5q13.2 dovodi do varijacija u broju kopija i strukturnih promena ne samo gena SMN, već i drugih prisutnih gena, poput SERF1 i NAIP, i one mogu uticati na tok i težinu bolesti. Dosadašnji podaci ukazuju na to da bi jednim delom uzrok fenotipskih razlika kod SMA mogao biti različit stepen metilacije promotora SMN2. Sporadična ALS (SALS) čini oko 90% svih slučajeva ALS i njena etiologija nije razjašnjena. Iako se genetička osnova, vreme pojave simptoma i tok SMA i SALS razlikuju, usled sličnosti patoloških promena i učešća proteina SMN i proteina asociranih sa ALS u zajedničkim molekularnim putevima, među genima kandidatima za nastanak i progresiju SALS velika pažnja usmerena je upravo na gene SMN. Cilj ove doktorske disertacije bio je ispitivanje genomske strukture, prirode rearanžmana i epigenetičkih oznaka u segmentalnoj duplikaciji 5q13.2 kod SMA bolesnika. Takođe, cilj je bio ispitivanje asocijacije broja kopija gena SMN1, SMN2, SERF1 i NAIP sa fenotipom dečije SMA, rizikom za nastanak SALS i preživljavanjem SALS bolesnika. U grupi od 99 SMA bolesnika i 122 roditelja bolesnika metodom umnožavanja većeg broja ligiranih proba (MLPA) analizirana su 442 hromozoma i id, Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are motor neurone diseases. SMA is the most frequent monogenic cause of infant mortality, whereas ALS is an incurable late-onset disease with an inexorably progressive course. SMA is caused by homozygous absence of the SMN1 gene located in the telomeric part of the 5q13.2 segmental duplication, while in its centromeric part resides a nearly identical copy named SMN2 producing only ~10% of functional SMN protein. Clinical presentation of SMA is extremely variable ranging from a severe infantile form (type I) to mild adult-onset form (type IV). Homogeneity of the disease-causing mutation and extensive phenotypic variability clearly indicate the existence of additional genetic, epigenetic and environmental factors modulating SMA phenotype. High rate of unequal crossing over in 5q13.2 segmental duplication results in copy number variations (CNVs) and complex structural rearrangements of the two SMN genes and other genes residing in the same region, such as SERF1 and NAIP, modulating disease progression and severity. Existing data suggest that, to some extent, phenotypic discrepancies in SMA might be due to differences in methylation level of the SMN2 promoter. Sporadic ALS (SALS) comprises ~90% of all ALS cases and has an unknown aetiology. Even though aetiology, age at onset and progression may differ between the diseases, due to similarities between ALS and SMA pathologies and the involvement of SMN and some ALS-associated proteins in common molecular pathways, SMN1 and SMN2 genes were repeatedly studied as SALS susceptibility genes. The aim of this doctoral thesis was to reconstruct genomic structure, the nature of rearrangements and epigenetic marks of the 5q.13.2 segmental duplication in SMA patients from Serbia. Furthermore, the aim was to investigate if copy numbers of the SMN1, SMN2, SERF1 and NAIP genes are associated with SMA type, susceptibility to SALS and survival in SALS patients from Se

The monitoring of progression in amyotrophic lateral sclerosis (ALS) relies on clinical outcome measures that take months to interpret, such as revised ALS functional rating scale (ALSFRS-R) score, with no approved biomarkers. A number of clinical studies have documented the involvement of oxidative stress in ALS pathology. Pertinent to this, we propose to evaluate oxidation-reduction potential (ORP) of cerebrospinal fluid (CSF) as a potential indicator of ALS progression. The case-control study included 24 patients with neurological non-neurodegenerative disorders (controls) and 82 ALS patients with different degrees of disease (ALSFRS-R score: 21-47). ORP was significantly higher in ALS patients than controls. It was not dependent on age or gender. A strong negative correlation was found between ORP and ALSFRS-R score for all patients and patients with spinal onset. In other words, ORP increased with ALS progression. No correlation was found for the subset of patients with bulbar onset, most likely because of the physical distance between neurodegenerative loci and the site of CSF collection. These results lead to the hypothesis that ORP of CSF has a potential as monitoring biomarker in ALS, particularly in the cohort of patients with spinal onset. Antioxid. Redox Signal. 00, 000-000.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with a very fast progression, no diagnostic tool for the presymptomatic phase, and still no effective treatment of the disease. Although ALS affects motor neurons, the overall pathophysiological condition points out to the non-cell autonomous mechanisms, where astrocytes and microglia play crucial roles in the disease progression. We have already shown that IgG from sera of ALS patients (ALS IgG) induce calcium transients and an increase in the mobility of acidic vesicles in cultured rat astrocytes. Having in mind the role of microglia in neurodegeneration, and a well-documented fact that oxidative stress is one of the many components contributing to the disease, we decided to examine the effect of ALS IgG on activation, oxidative stress and antioxidative system of BV-2 microglia, and to evaluate their acute effect on cytosolic peroxide, pH, and on reactive oxygen species (ROS) generation. All tested ALS IgGs (compared to control IgG) induced oxidative stress (rise in nitric oxide and the index of lipid peroxidation) followed by release of TNF-alpha and higher antioxidative defense (elevation of Mn- and CuZn-superoxide dismutase, catalase, and glutathione reductase with a decrease of glutathione peroxidase and glutathione) after 24 h treatment. Both ALS IgG and control IgG showed same localization on the membrane of BV-2 cells following 24 h treatment. Cytosolic peroxide and pH alteration were evaluated with fluorescent probes HyPer and SypHer, respectively, having in mind that HyPer also reacts to pH changes. Out of 11 tested IgGs from ALS patients, 4 induced slow exponential rise of HyPer signal, with maximal normalized fluorescence in the range 0.2-0.5, also inducing similar increase of SypHer intensity, but of a lower amplitude. None of the control IgGs induced changes with neither of the indicators. Acute ROS generation was detected in one out of three tested ALS samples with carboxy-H2DCFDA. T

Objectives: The aim of our study was to determine if redox imbalance caused by the activities of antioxidant enzymes existed in erythrocytes of type 1 myotonic dystrophy ( DM1) patients. Methods: The activities of erythrocyte superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were measured in 30 DM1 patients and 15 healthy controls ( HCs). The obtained values were correlated with the Muscular Impairment Rating Scale ( MIRS) score and creatine kinase ( CK). Results: Superoxide dismutase and catalase activities were lower in DM1 patients compared to HCs. A positive correlation was found between disease duration and MIRS score as well as with glutathione reductase activity. In DM1 patients, there were positive correlations between catalase, glutathione peroxidase, and glutathione reductase activities. After sub-dividing DM1 patients according to CK levels, superoxide dismutase activity was still statistically different from HCs. However, catalase activity was significantly lower only in DM1 patients with increased CK. Discussion: Undesirable alterations in antioxidant enzyme activities during DM1 disease progression may result in conditions favoring oxidative stress and changes in metabolism which together could contribute to muscle wasting.

In this work we compared the mutated liver copper zinc-containing superoxide dismutase (SOD1) protein G93A of the transgenic rat model of familial amyotrophic lateral sclerosis (FALS), to wild-type (WT) rat SOD1. We examined their enzymatic activities and effects on isometric contractions of uteri of healthy virgin rats. G93A SOD1 showed a slightly higher activity than WT SOD1 and, in contrast to WT SOD1, G93A SOD1 did not induce smooth muscle relaxation. This result indicates that effects on smooth muscles are not related to SOD1 enzyme activity and suggest that heterodimers of G93A SOD1 form an ion-conducting pore that diminishes the relaxatory effects of SOD1. We propose that this type of pathogenic feedback affects neurons in FALS.