leky-latky/gAD-glutamic-acid-decarboxylase/mechanismus-ucinku-vyznam

Ataxia

• Effects of GAD65Ab depend on the epitope specificity of the monoclonal GAD65Ab [3]
• Motor incoordination and impaired cognitive operations
• Monoclonal GAD65Ab
• Interfere with GABAergic neurotransmission in slice preparations
• Elicit neurophysiological and behavioral effects in animals that mimic CAs in vivo [3]
• Condition affects mostly women in their 60s
• GAD65Ab-associated CA can be subacute or chronic in terms of clinical presentation
• Patients exhibit gait and posture deficits, dysarthria, and nystagmus
• Association with type 1 diabetes mellitus (T1DM) is frequently observed
• Brain MRI of GAD65Ab-associated CA patients reveals only mild or no cerebellar atrophy [3]
• Oligoclonal bands and positivity for GAD65Ab
• Usually without elevation of cell and protein content
• Indicating intrathecal GAD65Ab production, rather than a compromised blood-brain barrier (BBB)
• Circulating GAD65Ab are often present with titers that exceed those typical for patients with T1DM by 10 to 100-fold [3]
• Induction therapies include
• Intravenous methylprednisolone
• Intravenous immunoglobulin (IVIg)
• Plasma exchange
• Rituximab to reduce the severity of symptoms
• Followed by maintenance therapy with
• Oral prednisolone,
• Azathioprine,
• Mycophenolate mofetil
• Repeated IVIg therapy
• Most patients with subacute CA
• Show clinical improvement after long-term therapy
• Patients with chronic CA
• Often show poor response with limited improvement or even progression of deficits during long-term follow-up
• Amelioration of CA-related clinical signs and symptoms following immunotherapy is associated with simultaneous decrease in GAD65Ab titers
• GAD65Ab-associated CAs are sometimes reported in paraneoplastic conditions [3]

Limbic encephalitis

Progressive encephalomyelitis with rigidity and myoclonus (PERM)

Autismus

• GAD65 and GAD67 experience significant downregulation in cases of autism
• Downregulation average of 50% in parietal and cerebellar cortices of autistic brains
• Cerebellar purjinke cells also reported a 40% downregulation
• Affected cerebellar nuclei may disrupt output to higher order motor and cognitive areas of the brain [2]

Diabetes

• GAD67 and GAD65 are targets of autoantibodies in people who later develop type 1 diabetes mellitus or latent autoimmune diabetes
• Injections with GAD65 in ways that induce immune tolerance have been shown to prevent type 1 diabetes in rodent models
• In clinical trials, injections with GAD65 have been shown to preserve some insulin production for 30 months in humans with type 1 diabetes.[2]
• GAD65Ab in T1DM
• Are strictly dependent on the conformation of the antigen [3]
• GAD65Ab in T1DM patients are only found in the periphery [3]
• Human monoclonal GAD65Ab b96.11
• Binds to a common epitope that is shared by GAD65Ab in patients with T1DM [ 3]
• Human monoclonal GAD65Ab b78
• Recognizes an epitope that is often recognized by GAD65Ab in patients with SPS and CA [3]
• Rarely recognized by GAD65Ab in patients with T1DM [3]
• Both monoclonal GAD65Ab recognize epitopes spanning the middle and C-terminal region of GAD65 [3]
• Reasons that GAD65 and not GAD67 is thought to function as an autoantigen in type I diabetes
• GAD65 autoantibodies are much more prevalent in patients with new-onset diabetes (70–90%versus ~10%)
• GAD67 autoreactivity most often occurs in patients who also exhibit autoreactivity to GAD65
• GAD67, unlike GAD65, is thought not to be synthesized in human islet cells
• Human islets produce a truncated variant: GAD25 [4]
• An increased incidence of autoreactivity to GAD67 has been noted in association with autoimmune polyglandular syndrome type II
• Commonly involves
• Adrenal cortex
• Islets (diabetes mellitus)
• Gonads [4]
• GAD25 is the only GAD67-like molecule expressed by all three of these tissues [4]
• Study showed that GADA-positive diabetic patients
• Have an increased risk of cognitive decline compared to patients with type 2 diabetes of comparable diabetic severity
• GADA may be associated with isolated cognitive decline in the absence of other neurological complications.
• bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-13-76
• Higher prevalence of GADA in nondiabetic adults (40.4%) have only been reported among workers exposed to polychlorinated biphenyl products.22 Similar prevalences have only been found for Indian patients with DM2
• www.ncbi.nlm.nih.gov/pmc/articles/PMC5428762/

Epilepsy

• Pattern of anti-GAD antibodies in epilepsy differs from type 1 diabetes and stiff-person syndrome [2]

Mozek

• GABA is the major inhibitory transmitter in the mammalian brain
• Gamma-aminobutyric acid (GABA) as transmitter and expression of GAD - rate limiting enzyme [1]

Isoenzymes in CNS

• GAD65
• GAD67
• Seem to provide a dual system for the control of neuronal GABA synthesis [1]

Lokalizace

• Majority of neurons in the striatum
• Caudate-putamen,
• Dorsal striatum;
• Nucleus accumbens,
• Ventral striatum
• Striatal projection regions
• Pallidum,
• Entopeduncular nucleus
• Substantia nigra reticulata
• Can be distinguished in both dorsal and ventral striatum as well as in other parts of the basal ganglia [1]

Striatum

• Two populations of medium-sized GABA neurons in the striatum seem to be under tonic dopaminergic influence
• Majority of these GABA neurons are under inhibitory influence
• Small number seem to be stimulated by dopamine
• Specific changes in activity in subpopulations of striatal GABA neurons
• Probably mediate the dopamine-dependent hypokinetic syndrome seen in Parkinson's disease and following neuroleptic treatment

Inhibition of dopaminergic transmission

• By lesion of dopamine neurons or by neuroleptic treatment
• Followed by an
• Increased release of GABA
• Increased expression of GAD67 mRNA in a subpopulation of striatal medium-sized neurons
• Project to the globus pallidus
• Increased striatal GAD enzyme activity [1]

Increased dopaminergic transmission

• By repeated but not single doses of amphetamine
• Followed by
• Decreased striatal GABA release
• Decreased GAD67 mRNA expression in a subpopulation of medium-sized neurons in the striatum [1]

Neuropathic pain

• Peripheral nerve injury of the sciatic nerve (a neuropathic pain model)
• Induces a transient loss of GAD65 immunoreactive terminals in the spinal cord dorsal horn
• Suggests a potential involvement for these alterations in the development and amelioration of pain behaviour [2]

Parkinson disease

• Bilateral delivery of glutamic acid decarboxylase (GAD) by an adeno-associated viral vector into the subthalamic nucleus
• Of patients between 30 and 75 years of age with advanced, progressive, levodopa-responsive Parkinson disease
• Resulted in significant improvement over baseline during the course of a six-month study

Cerebellar disorders

• Intracerebellar administration of GAD autoantibodies to animals
• Increases the excitability of motoneurons
• Impairs the production of nitric oxide (NO), a molecule involved in learning
• Epitope recognition contributes to cerebellar involvement
• Reduced GABA levels increase glutamate levels as a consequence of lower inhibition of subtypes of GABA receptors.
• Higher glutamate levels activate microglia and activation of xc(-) increases the extracellular glutamate release. [2]

Cesta zrychleného poškožení neronů vylývajících glutamát a tedy porucha učení - demence

• Possible Molecular Changes Leading to Cerebellar Atrophy.
• The pathogenic mechanisms leading to cerebellar atrophy have been examined in vivo [3]
• The N-methyl-D-aspartate- (NMDA-) mediated calcium entry at postsynaptic densities is coupled with nitric oxide (NO) synthesis
• In turn inhibits glutamate release
• Thereby preventing excitotoxic neuronal death
• Intracerebellar administration of CSF IgGs
• Specifically reduces the NMDA-mediated production of NO
• Impairs the synaptic regulation of glutamate after NMDA administration
• Thereby potentially facilitating pathological processes that lead to cerebellar atrophy by excitotoxicity [3]
• CSF IgGs elicit dual impairments:
• Depression of receptor-mediated inhibitory synaptic transmission
• Attenuation of receptor-mediated inhibition of excitatory transmission [3]

GAD rostlin (citrusy)

• Glutamate decarboxylase plays a key role in citrate metabolism
• With the increase of glutamate decarboxylase via direct exposure, citrate levels have been seen to significantly increase within plants
• In conjunction post-harvest quality maintenance was significantly improved, and rot rates decreased [2]

Schizophrenia and bipolar disorder

• Substantial dysregulation of GAD mRNA expression, coupled with downregulation of reelin
• Observed in schizophrenia and bipolar disorder
• Most pronounced downregulation of GAD67 was found in
• Hippocampal stratum oriens layer in both disorders
• Other layers and structures of hippocampus with varying degrees [2]
• People with schizophrenia have been shown to express lower amounts of GAD67 in the
• Dorsolateral prefrontal cortex compared to healthy controls
• Mechanism underlying the decreased levels of GAD67 in people with schizophrenia remains unclear
• Immediate early gene, Zif268
• Normally binds to the promoter region of GAD67 and increases transcription of GAD67
• Is lower in schizophrenic patients
• Dorsolateral prefrontal cortex (DLPFC) is involved in working memory
• GAD67 and Zif268 mRNA levels are lower in the DLPFC of schizophrenic patients
• Working memory impairments associated with the disease.

Stiff person syndrome (SPS)

• High titers of autoantibodies to glutamic acid decarboxylase (GAD)
• Rate-limiting enzyme in the synthesis of gama-aminobutyric acid (GABA)
• Impaired function of GABA-ergic neurons has been implicated in the pathogenesis of SPS
• Autoantibodies to GAD might be the causative agent or a disease marker. [2]
• GAD65Ab titers in SPS
• Exceed those in T1DM by up to 500-fold
• Recognize linear epitopes [3]