Brain Iron Accumulation Type Research Articles

Neuropathology, biochemistry, and biophysics of α‐synuclein aggregation

Aggregation of alpha-synuclein, an abundant and conserved pre-synaptic brain protein, is implicated as a critical factor in several neurodegenerative diseases. These diseases, known as synucleinopathies, include Parkinson's disease, dementia with Lewy bodies (LBs), diffuse LB disease, the LB variant of Alzheimer's disease, multiple system atrophy, and neurodegeneration with brain iron accumulation type I. Although the precise nature of in vivoalpha-synuclein function remains elusive, considerable knowledge has been accumulated about its structural properties and conformational behavior. alpha-Synuclein is a typical natively unfolded protein. It is characterized by the lack of rigid, well-defined, 3-D structure and possesses remarkable conformational plasticity. The structure of this protein depends dramatically on its environment and it accommodates a number of unrelated conformations. This paper provides an overview of the biochemistry, biophysics, and neuropathology of alpha-synuclein aggregation.

Anesthesia for patients with pantothenate-kinase-associated neurodegeneration (Hallervorden-Spatz disease) - a literature review.

Hallervorden-Spatz disease (HSD) is a rare, progressive neurodegenerative disorder; the new and preferred name for HSD is 'pantothenate-kinase-associated neurodegeneration' (PKAN). Other suggested names are 'neurodegeneration with brain iron accumulation type 1' or 'infantile neuroaxonal dystrophy'. Patients with PKAN have many complications, which lead to numerous anesthetic management challenges. Reports concerning the anesthetic management of patients with PKAN are very limited. To determine the anesthetic management and techniques as well as relevant complications for patients with PKAN. In this study, we review previously published literature regarding the anesthesia-relevant clinical symptoms, the anesthetic management and techniques, and possible complications for this disorder. Only four studies describing the anesthetic management and anesthetic techniques in patients with PKAN were found. Anesthesia-relevant symptoms influence the preanesthetic management (eg difficulties in articulation, dementia), the induction of anesthesia (eg oromandibular rigidity, seizures, dysphagia, aspiration) and the postoperative care (eg respiratory disability). Reports concerning the anesthetic management of patients with PKAN are very limited, possibly as a result of the rareness of the disorder. Like many other patients with neurodegenerative diseases, patients with PKAN have many anesthesia-relevant symptoms, leading to numerous anesthetic management challenges. In general, the anesthetic complications associated with PKAN are usually no different from those associated with other neurodegenerative diseases, and the management of these are usually concordant.

α-Synuclein: Normal Function and Role in Neurodegenerative Diseases

Synucleins are a family of small, highly charged proteins expressed predominantly in neurons. Since their discovery and characterization during the last decade, much has been learned about their structure, potential functions, interactions with other proteins, and roles in disease. One of these proteins, alpha-synuclein (alpha-syn), is the major building block of pathological inclusions that characterize many neurodegenerative disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and neurodegeneration with brain iron accumulation type 1 (NBIA-1), which collectively are termed synucleinopathies. Furthermore, genetic and biological studies support a role for alpha-syn in the pathophysiology of these diseases. Therefore, research must be continued in order to better understand the functions of the synuclein proteins under normal physiological conditions as well as their role in diseases.

Neuropathological spectrum of synucleinopathies.

Synucleinopathies comprise a diverse group of neurodegenerative proteinopathies that share common pathological lesions composed of aggregates of conformational and posttranslational modifications of alpha-synuclein in selected populations of neurons and glia. Abnormal filamentous aggregates of misfolded alpha-synuclein protein are the major components of Lewy bodies, dystrophic (Lewy) neurites, and the Papp-Lantos filaments in oligodendroglia and neurons in multiple system atrophy linked to degeneration of affected brain regions. The synucleinopathies include (1) Lewy body disorders and dementia with Lewy bodies, (2) multiple system atrophy (MSA), and (3) Hallervorden-Spatz disease. (1) The pathological diagnosis of Lewy body disorders and dementia with Lewy bodies is established by validated consensus criteria based on semiquantitative assessment of subcortical and cortical Lewy bodies as their common hallmarks. They are accompanied by subcortical multisystem degeneration with neuronal loss and gliosis with or without Alzheimer pathologic state. Lewy bodies also occur in numerous other disorders, including pure autonomic failure, neuroaxonal dystrophies, and various amyloidoses and tauopathies. (2) Multiple system atrophy, a sporadic, adult-onset degenerative movement disorder of unknown cause, is characterized by alpha-synuclein-positive glial cytoplasmic and rare neuronal inclusions throughout the central nervous system associated with striatonigral degeneration, olivopontocerebellar atrophy, and involvement of medullar and spinal autonomic nuclei. (3) In neurodegeneration with brain iron accumulation type I, or Hallervorden-Spatz disease, alpha-synuclein is present in axonal spheroids and glial and neuronal inclusions. While the identity of the major components of Lewy bodies suggests that a pathway leading from normal soluble to abnormal misfolded filamentous proteins is central for their pathogenesis, regardless of the primary disorder, there are conformational differences in alpha-synuclein between neuronal and glial aggregates, showing nonuniform mapping for its epitopes. Despite several cellular and transgenic models, it is not clear whether inclusion body formation is an adaptive/neuroprotective or a pathogenic reaction/process generated in response to different, mostly undetermined, functional triggers linked to neurodegeneration.

Transgenic Models of α‐Synuclein Pathology

Accumulation and toxic conversion to protofibrils of alpha-synuclein has been associated with neurological disorders such as Parkinson's disease (PD), Lewy body disease, multiple system atrophy, neurodegeneration with brain iron accumulation type 1, and Alzheimer's disease. In recent years, modeling these disorders in transgenic (tg) mice and flies has helped improve understanding of the pathogenesis of these diseases and has established the basis for the development of new experimental treatments. Overexpression of alpha-synuclein in tg mice in a region- and cell-specific manner results in degeneration of selective circuitries accompanied by motor deficits and inclusion formation similar to what is found in PD and related disorders. Furthermore, studies in singly and doubly tg mice have shown that toxic conversion and accumulation can be accelerated by alpha-synuclein mutations associated with familial parkinsonism, by amyloid beta peptide 1-42 (Abeta 1-42), and by oxidative stress. In contrast, molecular chaperones such as Hsp70 and close homologues such as alpha-synuclein have been shown to suppress toxicity. Similar studies are underway to evaluate the effects of other modifying genes that might play a role in alpha-synuclein ubiquitination. Among them considerable interest has been placed on the role of molecules associated with familial parkinsonism (Parkin, UCHL-1). Furthermore, studying the targeted overexpression of alpha-synuclein and other modifier genes in the nigrostriatal and limbic system by using regulatable promoters, lentiviral vectors, and siRNA will help improve understanding of the molecular mechanisms involved in selective neuronal vulnerability, and it will aid the development of new treatments.

Selective Insolubility of α-Synuclein in Human Lewy Body Diseases Is Recapitulated in a Transgenic Mouse Model

alpha-Synuclein (alpha-SYN) is deposited in intraneuronal cytoplasmic inclusions (Lewy bodies, LBs) characteristic for Parkinson's disease (PD) and LB dementias. alpha-SYN forms LB-like fibrils in vitro, in contrast to its homologue beta-SYN. Here we have investigated the solubility of SYNs in human LB diseases and in transgenic mice expressing human wild-type and PD-associated mutant [A30P]alpha-SYN driven by the brain neuron-specific promoter, Thy1. Distinct alpha-SYN species were detected in the detergent-insoluble fractions from brains of patients with PD, dementia with LBs, and neurodegeneration with brain iron accumulation type 1 (formerly known as Hallervorden-Spatz disease). Using the same extraction method, detergent-insolubility of human alpha-SYN was observed in brains of transgenic mice. In contrast, neither endogenous mouse alpha-SYN nor beta-SYN were detected in detergent-insoluble fractions from transgenic mouse brains. The nonamyloidogenic beta-SYN was incapable of forming insoluble fibrils because amino acids 73 to 83 in the central region of alpha-SYN are absent in beta-SYN. In conclusion, the specific accumulation of detergent-insoluble alpha-SYN in transgenic mice recapitulates a pivotal feature of human LB diseases.

HGFRα-4: a new member of the GDNF receptor family and a candidate for NBIA

Hallervorden-Spatz syndrome (neurodegeneration with brain iron accumulation type 1; OMIM entry 234200) is a rare inherited neurodegenerative disease. In this article, evidence for a newly identified gene as a candidate for Hallervorden-Spatz syndrome is given. Previously Hallervorden-Spatz syndrome was mapped to a 4-cm region in 20p12.3-13. During positional cloning efforts a new member of the glial-derived neurotrophic factor receptor family was discovered in this region. Like other members of this receptor family, this new gene is predicted to be secreted and glycosyl-phosphatidylinositol linked, and it maintains conserved cysteine residues. However, cDNA and genomic studies in both humans and mice indicate that this gene lacks the sequence corresponding to exons 2 and 3 in other family members. In situ hybridization reveals that it is expressed primarily in the brain and bladder in the embryonic mouse. Mutation analysis of patients with Hallervorden-Spatz syndrome revealed two potentially significant amino acid changes in two patients but failed to identify mutations in the remaining 10 subjects. The implication of these findings for the relationship between this gene and Hallervorden-Spatz syndrome is discussed.

Widespread Nitration of Pathological Inclusions in Neurodegenerative Synucleinopathies

Reactive nitrogen species may play a mechanistic role in neurodegenerative diseases by posttranslationally altering normal brain proteins. In support of this hypothesis, we demonstrate that an anti-3-nitrotyrosine polyclonal antibody stains all of the major hallmark lesions of synucleinopathies including Lewy bodies, Lewy neurites and neuraxonal spheroids in dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and neurodegeneration with brain iron accumulation type 1, as well as glial and neuronal cytoplasmic inclusions in multiple system atrophy. This antibody predominantly recognized nitrated alpha-synuclein when compared to other in vitro nitrated constituents of these pathological lesions, such as neurofilament subunits and microtubules. Collectively, these findings imply that alpha-synuclein is nitrated in pathological lesions. The widespread presence of nitrated alpha-synuclein in diverse intracellular inclusions suggests that oxidation/nitration is involved in the onset and/or progression of neurodegenerative diseases.

Neuropathology of synuclein aggregates.

Beginning with the isolation of the fragment of alpha-synuclein (alpha-syn) known as the non-Abeta component of amyloid plaques (NAC peptide) from Alzheimer's disease (AD) brains, alpha-syn has been increasingly implicated in the pathogenesis of neurodegenerative diseases, which now are classified as synucleinopathies. Indeed, unequivocal evidence linking abnormal alpha-syn to mechanisms of brain degeneration came from discoveries of missense mutations in the alpha-syn gene pathogenic for familial Parkinson's disease (PD) in rare kindreds. Shortly thereafter, alpha-syn was shown to be a major component of Lewy bodies (LBs) and Lewy neurites in sporadic PD, dementia with LBs (DLB) and the LB variant of AD. Also, studies of brains from patients with AD caused by genetic abnormalities demonstrated many alpha-syn positive LBs. Further, alpha-syn was implicated in the formation of the glial (GCIs) and neuronal cytoplasmic inclusions of multiple system atrophy, and the LBs, GCIs and neuraxonal spheroids of neurodegeneration with brain iron accumulation type 1. Recently, two other members of the synuclein family, beta- and gamma-synuclein, have also been recognized to play a role in the pathogenesis of novel axonal lesions in PD and DLB. Evidence for a role of alpha-syn in the formation of filamentous aggregates was reinforced by in vitro studies showing aggregation and fibrillogenesis of mutant and wild type alpha-syn. Indeed, since the aggregation of brain proteins into presumptively toxic lesions is emerging as a common but poorly understood mechanistic theme in sporadic and hereditary neurodegenerative diseases, clarification of the mechanism of synuclein aggregation could augment efforts to develop novel and more effective therapies for many neurodegenerative disorders.

Lewy body in neurodegeneration with brain iron accumulation type 1 is immunoreactive for alpha-synuclein.

In familial PD, a mutation of the alpha-synuclein gene has been identified. Alpha-synuclein also was revealed in Lewy bodies in idiopathic PD. Lewy bodies in neurodegeneration with brain iron accumulation type 1 (NBIA 1; Hallervorden-Spatz syndrome) were found to show immunostaining for alpha-synuclein/precursor of non-A beta component of Alzheimer's disease amyloid, indicating that alpha-synuclein is commonly associated with the formation of Lewy bodies in other sporadic and familial neurodegenerative diseases apart from PD.

Effects of ablation of flocculus and paraflocculus of eye movements in primate.

1. Eye movements were recorded in four rhesus monkeys, before and after bilateral ablations of the flocculi and portions of the paraflocculi (“flocculectomy”). Animals were trained to fixate and follow targets so that pursuit, saccades, and vestibular and optokinetic nystagmus could be quantitated. 2. The vestibuloocular reflex (VOR) was mildly affected by flocculectomy. In darkness the VOR gain (eye velocity/head velocity) for steps of head velocity (normal range, 0.84-0.96) increased postoperatively in one monkey to 1.17, decreased in another to 0.62, and did not change significantly in the other two (0.96, 0.94). VOR phase lead at 0.05-Hz oscillation in darkness (normal range, O,O--LOO) increased in two monkeys by 12 and 9.5 O but did not change significantly in the others. 3. Visual suppression of inappropriate vestibular nystagmus was impaired. During oscillation at 0.25 Hz with a head-fixed visual scene, the average amount of attenuation of the VOR decreased from 5 1% preoperatively to 20% postoperatively. Visual suppression of caloric nystagmus was comparably affected. 4. Smooth tracking of small targets moving in space was impaired either with the head still (smooth pursuit) or moving (cancellation of the VOR by fixating a target rotating with the head). The average gain (gaze velocity/target velocity) in either case was about 0.65 (normal, 0.95-0.98). The pursuit deficit was less than that reported after total cerebellectomy, suggesting other cerebellar structures also participate in smooth tracking. 5. Optokinetic nystagmus (OKN) was present postoperatively but, in response to a constant-velocity stimulus, the initial slowphase velocity decreased by 50% and the rise time to a steady state nearly doubled. For stimuli belowr 6O”/s the average steady-state gain was only mildly diminished to 0.86 (normal, 0.98) and the time course of optokinetic afternystagmus (OKAN) in darkness was normal. The response to higher velocity optokinetic stimuli was impaired. These abnormalities can largely be attributed to the coexisting pursuit deficit although the protracted rise to a steady state suggests a change in the ability of the brain stem optokinetic system to handle large amounts of retinal slip. 6. Flocculectomized monkeys showed horizontally, gaze-paretic nystagmus with exponentially decaying centripetal drift (time constant, 1.56 s) and vertically, downbeat nystagmus with exponentially decaying (in three monkeys) or exponentially increasing (in one monkey) slow phases. All animals showed rebound nystagmus. These results implicate the flocculus and possibly the paraflocculus in the control of the time constant and stability of the brain stem oculomotor integrators. 7. Saccadic velocities and accuracy were normal but flocculectomized monkeys showed brief (40150 ms duration), approximately exponential, postsaccadic drift with amplitudes up to 15% of the size of the saccade. The eyes usually drifted in the same direction as the saccade but each monkey showed an idiosyncratic pattern depending on saccade direction and eye position. Postsaccadic drift may reflect a mismatch between the phasic (pulse) and tonic (step) innervational changes that create saccades.