The neurobiology of duchenne muscular dystrophy: learning lessons from muscle?

Several forms of inherited muscular dystrophy are associated with brain abnormalities and cognitive impairment. One of the most common and severe of these diseases is Duchenne muscular dystrophy (DMD). Dystrophin, the product of the DMD gene, is found in neurones, where it is associated with the postsynaptic membrane. Cognitive impairment in individuals with DMD is thought to be due to an abnormality in the neuronal membrane that is caused by lack of dystrophin. Recent experimental evidence has provided valuable clues in our understanding of the complex molecular neurobiology of muscular dystrophy.     

Pig models for Duchenne muscular dystrophy – from disease mechanisms to validation of new diagnostic and therapeutic concepts

Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the DMD gene, leading to complete absence of dystrophin and progressive degeneration of skeletal muscles and heart. Animal models are essential for preclinical evaluation of novel diagnostic procedures and treatment strategies. Gene targeting/editing offers the possibility of developing tailored pig models for monogenic diseases. The first porcine DMD model was generated by deletion of DMD exon 52 (DMDΔ52) in cultured kidney cells, which were used for somatic cell nuclear transfer to produce DMDΔ52 offspring. The animals resembled clinical, biochemical, and pathological hallmarks of DMD, but died before sexual maturity, thus preventing their propagation by breeding. This limitation was overcome by the generation of female heterozygous DMDΔ52 carrier pigs, which allowed the establishment of a large breeding colony. In this overview, we summarize how porcine DMD models have been used for dissecting disease mechanisms, for validating multispectral optoacoustic tomography as an imaging modality for monitoring fibrosis, and for preclinical testing of a CRISPR/Cas9 based approach to restore an intact DMD reading frame. Particular advantages of porcine DMD models include their targeted design and the rapid disease progression with early cardiac involvement, facilitating translational studies in reasonable time frames.     

Facioscapulohumeral (FSHD1) and other forms of muscular dystrophy in the same family: is there more in muscular dystrophy than meets the eye?

We report on two unrelated Brazilian families with members affected by two different forms of muscular dystrophy. In the first one, the 35-year-old male proband has limb-girdle muscular dystrophy with proximal weakness, elevated creatine kinase and a myopathic muscle biopsy. All the proteins known to be associated with limb-girdle muscular dystrophy were normal. Two of his sisters also complained of muscle weakness. The oldest sister showed clinical signs consistent with facioscapulohumeral muscular dystrophy, confirmed through molecular analysis. She presented a 30 kb EcoRI/BlnI fragment which was found in another six relatives, but surprisingly not in the affected proband or the other sister. In the second family, a 57-year-old male with a typical facioscapulohumeral muscular dystrophy phenotype has a 17 kb EcoRI/BlnI fragment, which was also present in other affected relatives. However in a 14-year-old severely affected male cousin, confined to a wheelchair since age 12, but without facial weakness, the small fragment was absent. These families illustrate the importance of testing all affected individuals in a family.     

Cell and molecular neurobiology of presenilins: A role for the endoplasmic reticulum in the pathogenesis of Alzheimer's disease?

Mutations in genes encoding presenilin-1 (PS-1) and presenilin-2 (PS-2) cause many cases of autosomal dominant inherited forms of early-onset Alzheimer's disease (AD). PSs are expressed in neurons throughout the nervous system, with differences in abundance among cell populations. PS-1 and PS-2 each have six to eight transmembrane domains and are localized mainly in the endoplasmic reticulum (ER). PSs may interact with cytoskeletal proteins and β-amyloid precursor protein (APP) in ways consistent with roles in membrane trafficking and APP processing. Expression of mutant PSs in cultured cells and transgenic mice results in increased production of an amyloidogenic-cytotoxic form of amyloid β-peptide (Aβ). Neural cells expressing mutant PSs exhibit increased sensitivity to apoptosis induced by trophic factor withdrawal and Aβ. The proapoptotic action of mutant PSs involves perturbed calcium release from ER stores and increased levels of oxidative stress. PS mutations may also suppress neurotransmitter synthesis in cholinergic neurons, suggesting a role in regulation of neuronal phenotype. Homology of PSs with the C. elegans gene sel-12 and phenotypic similarities of PS-1 and Notch knockout mice suggest a developmental role for PSs in somitogenesis. Collectively, the emerging data suggest intriguing roles of PSs in neuronal plasticity and cell death and highlight the importance of the ER as a regulatory site involved in the pathogenesis of neuronal degeneration in AD. J. Neurosci. Res. 50:505–513, 1997. © 1997 Wiley-Liss, Inc.     

Lipids and the pathogenesis of Alzheimer's disease: is there a link?

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder characterized pathologically by amyloid-beta plaques, neurofibrillary tangles and neuronal loss. Its fundamental cause(s) and the pathological cascades leading to clinical symptoms remain unknown. Lipids and lipid peroxidation products have important roles in the homeostasis of the central nervous system. As well, lipid transport genes and vascular changes associated with peripheral dyslipidemia have been associated with an increased risk of AD. The present review discusses ways in which lipids may be involved in the pathogenesis of AD-associated neurodegeneration through their roles as neuronal structural components, cell modulators, or second messengers. Given the many possibilities through which lipids may be directly involved in or contribute to the pathogenesis of AD, the use of lipids as biomarkers for disease progression is discussed, as are other avenues for future research.     

Myogenic stem cells from the bone marrow: a therapeutic alternative for muscular dystrophy?

Differentiated muscle fibres can be formed by transplanted haematopoietic stem cells in models of acute or chronic muscle regeneration, including the dystrophin-deficient mdx mouse. Muscle-forming activity can be found in adult, foetal and embryonic haematopoietic tissues. The blood-to-muscle transition may be due to transdifferentiation of haematopoietic progenitors in response to local signals provided by the regenerating muscle. These signals are only poorly provided by the muscle of the mdx mouse, since transplantation into these mice of normal C57Bl/6 bone marrow gives rise only to a minimal number of muscle fibres expressing the normal dystrophin protein (<1%) throughout the animal life span. Expansion and active recruitment to myogenic differentiation of transplanted haematopoietic cells are therefore critical factors for a future use of bone marrow transplantation in cell/gene therapy of muscular dystrophy.     

Is the carboxyl-terminus of dystrophin required for membrane association? A novel,severe case of duchenne muscular dystrophy

Duchenne muscular dystrophy is a lethal X-linked recessive disorder caused by the deficiency of a component of the muscle fiber membrane cytoskeleton called dystrophin. Becker muscular dystrophy, a clinically milder disorder, results from dystrophin abnormalities rather than deficiency. We identified the first patient who is clearly an exception to these established clinical and biochemical correlates. The patient described clinically had particularly severe Duchenne dystrophy. Biochemically, his muscle contained substantial amounts of abnormal dystrophin (Becker-like). Characterization of the dystrophin protein and gene revealed a unique intragenic gene deletion resulting in a dystrophin protein missing the carboxyl-terminal domain. This patient's dystrophin seemed to have a deleterious "dominant" effect on his muscle: The presence of this abnormal protein was more damaging to the myofibers than the absence of dystrophin would have been. This patient challenges the current hypothesis that dystrophin associates with the plasma membrane solely via its carboxyl-terminus, yet supports the hypothesis that an intact carboxyl-terminus is crucial for correct dystrophin function.     

Thienopyridines or aspirin to prevent stroke and other serious vascular events in patients at high risk of vascular disease? A systematic review of the evidence from randomized trials

BACKGROUND AND PURPOSE: Aspirin is the most widely studied and prescribed antiplatelet drug for patients at high risk of vascular disease. We aimed to establish how the thienopyridines (ticlopidine and clopidogrel) compare with aspirin in terms of effectiveness and safety. METHODS: We did a systematic review of all unconfounded randomized trials comparing either ticlopidine or clopidogrel with aspirin for patients at high risk of vascular disease. The primary outcome was vascular events (stroke, myocardial infarction, or vascular death). Adverse outcomes were intracranial and extracranial hemorrhage, upper and lower gastrointestinal disturbances, neutropenia, thrombocytopenia, and skin rash. RESULTS: In 4 trials among 22 656 patients (including 9840 presenting with a transient ischemic attack/ischemic stroke), the thienopyridines reduced the odds of a vascular event by 9% (odds ratio 0.91, 95% CI 0.84 to 0. 98; 2P=0.01), preventing 11 (95% CI 2 to 19) events per 1000 patients treated for approximately 2 years. The thienopyridines produced significantly less gastrointestinal hemorrhage and upper gastrointestinal upset (indigestion/nausea/vomiting) than did aspirin. Both thienopyridines increased the odds of skin rash and of diarrhea (ticlopidine by approximately 2-fold and clopidogrel by approximately one third). Only ticlopidine increased the odds of neutropenia. CONCLUSIONS: The thienopyridines appear modestly more effective than aspirin in preventing serious vascular events in high-risk patients. Clopidogrel appears to be safer than ticlopidine and as safe as aspirin, making it an appropriate, but more expensive, alternative antiplatelet drug for patients unable to tolerate aspirin. However, there is insufficient information to determine which particular types of patients would benefit most, and which least, from clopidogrel instead of aspirin.     

A case of Gerstmann-Str?ussler-Scheinker disease with severe muscular atrophy and vertical gaze palsy]

Here we report a case of 56-year-old man with Gerstmann-Str?ussler-Scheinker disease (GSS). He had gait disturbance, limb and truncal ataxia, dysarthria and dysphagia at the age of 53. When he developed vertical gaze palsy and dystonic posture of the neck, subcortical dementia, progressive supuranuclear palsy was suspected. Thereafter dementia rapidly progessed, and CT scan showed severe atrophy of the brain. Since severe muscular atrophy and fasciculation also appeared, and abnormality in the codon 102 of prion protein gene was found, he was diagnosed to have the classical type of GSS. GSS with vertical gaze palsy has never been reported, and involvement of the lower motor neuron is also very rare. Therefore, the present case is an atypical type of GSS.     

Is the distinction between Alzheimer's disease and vascular dementia possible and relevant?

Advances in epidemiological, clinical, imaging, and neuropathological studies have undermined the clear distinction between vascular and Alzheimer-type dementia, which has characterized the last two decades of research in dementia. A significant degree of overlap between the two entities was demonstrated in terms of clinical expression, risk factors, and postmortem brain autopsy. In this article, we propose mechanisms by which cardiovascular risk factors might affect the manifestation of Alzheimer's disease, suggest possible explanations for the overlap with vascular dementia, and discuss the implications this might have on future differential diagnosis and treatment strategies.     

Does perfusion CT enable differentiating Alzheimer's disease from vascular dementia and mixed dementia? A preliminary report

The purpose of the study was to evaluate the usefulness of perfusion CT (pCT) in differentiating Alzheimer's disease (AD) from vascular dementia (VaD) and mixed dementia (MixD). pCT was performed in 41 patients (mean age, 68.3 years): 24 with AD, 8 with VaD, and 9 with MixD. Regional perfusion parameters (rCBF, rCBV, and rMTT) were calculated from 31 ROIs in the grey and white matter of the frontal and temporal lobes, basal ganglia, and internal capsules bilaterally. The obtained data for the subgroups of AD, VaD, and MixD patients were compared statistically. CONCLUSIONS: On the basis of rCBF and rCBV values, pCT may be a valuable method of distinguishing between AD and VaD but it seems to be of little significance in differentiating MixD from VaD and of no usefulness in distinguishing between AD and MixD.     

Genetic and environmental factors in the pathogenesis of Huntington’s disease

Huntingtons disease is a fatal inherited disorder in which there is progressive neurodegeneration in specific brain areas, mainly the striatum and cerebral cortex, producing motor, cognitive, and psychiatric symptoms. The trinucleotide repeat mutation involved is common to many other brain diseases, which may therefore involve similar mechanisms of pathogenesis. We are beginning to understand how a CAG trinucleotide repeat expansion in the disease gene, encoding an expanded polyglutamine tract, induces neuronal dysfunction and symptomatology in Huntingtons disease. Recent evidence that environmental factors modify the onset and progression of neurodegeneration has shed new light on Huntingtons disease and other devastating brain diseases. This review focuses on genetic mediators, environmental modulators, and associated gene-environment interactions in the pathogenesis of Huntingtons disease.     

A further update on the role of excitotoxicity in the pathogenesis of Parkinson’s disease

Increased levels of extracellular glutamate and hyperactivation of glutamatergic receptors in the basal ganglia trigger a critical cascade of events involving both intracellular pathways and cell-to-cell interactions that affect cell viability and promote neuronal death. The ensemble of these glutamate-triggered events is responsible for excitotoxicity, a phenomenon involved in several pathological conditions affecting the central nervous system, including a neurodegenerative disease such as Parkinson’s disease (PD). PD is an age-related disorder caused by the degeneration of dopaminergic neurons within the substantia nigra pars compacta, with a miscellaneous pathogenic background. Glutamate-mediated excitotoxicity may be involved in a lethal vicious cycle, which critically contributes to the exacerbation of nigrostriatal degeneration in PD. Since excitotoxicity is a glutamate-receptor-mediated phenomenon, growing interest and work have been dedicated to the research for modulators of glutamate neurotransmission that might enable new therapeutic interventions to slow down the neurodegenerative process and ameliorate PD motor symptoms.