Nerves, brain cells and spinal cord
Dock3 protects myelin in the cuprizone model for demyelination.
Namekata K, Kimura A, Harada C, Yoshida H, Matsumoto Y, Harada T.
Dedicator of cytokinesis 3 (Dock3) belongs to an atypical family of the guanine nucleotide exchange factors. It is predominantly expressed in the neural tissues and causes cellular morphological changes by activating the small GTPase Rac1.
We previously reported that Dock3 overexpression protects retinal ganglion cells from excitotoxic cell death. Oligodendrocytes are the myelinating cells of axons in the central nervous system and these cells are damaged in demyelinating disorders including multiple sclerosis (MS) and optic neuritis.
In this study, we examined if Dock3 is expressed in oligodendrocytes and if increasing Dock3 signals can suppress demyelination in a cuprizone-induced demyelination model, an animal model of MS.
We demonstrate that Dock3 is expressed in oligodendrocytes and Dock3 overexpression protects myelin in the corpus callosum following cuprizone treatment. Furthermore, we show that cuprizone demyelinates optic nerves and the extent of demyelination is ameliorated in mice overexpressing Dock3.
Cuprizone treatment impairs visual function, which was demonstrated by multifocal electroretinograms, an established non-invasive method, and Dock3 overexpression prevented this effect.
In mice overexpressing Dock3, Erk activation is increased, suggesting this may at least partly explain the observed protective effects.
Our findings suggest that Dock3 may be a therapeutic target for demyelinating disorders including optic neuritis.
Source: Cell Death and Disease (2014) 5, e1395; doi:10.1038/cddis.2014.357 & Pubmed PMID: 25165881 (09/09/14)
Axonal degeneration in multiple sclerosis: can we predict and prevent permanent disability?
Lee J, Taghian K, Petratos S.
Axonal degeneration is a major determinant of permanent neurological impairment during multiple sclerosis (MS). Due to the variable course of clinical disease and the heterogeneity of MS lesions, the mechanisms governing axonal degeneration may differ between disease stages.
While the etiology of MS remains elusive, there now exist potential prognostic biomarkers that can predict the conversion to clinically definite MS.
Specialised imaging techniques identifying axonal injury and drop-out are becoming established in clinical practice as a predictive measure of MS progression, such as optical coherence tomography (OCT) or diffusion tensor imaging (DTI). However, these imaging techniques are still being debated as predictive biomarkers since controversy surrounds their lesion-specific association with expanded disability status scale (EDSS).
A more promising diagnostic measure of axonal degeneration has been argued for the detection of reduced N-acetyl aspartate (NAA) and Creatine ratios via magnetic resonance spectroscopic (MRS) imaging, but again fail with its specificity for predicting actual axonal degeneration. Greater accuracy of predictive biomarkers is therefore warranted and may include CSF neurofilament light chain (NF-L) and neurofilament heavy chain (NF-H) levels, for progressive MS. Furthermore, defining the molecular mechanisms that occur during the neurodegenerative changes in the various subgroups of MS may in fact prove vital for the future development of efficacious neuroprotective therapies.
The clinical translation of a combined Na+ and Ca2+ channel blocker may lead to the establishment of a bona fide neuroprotective agent for the treatment of progressive MS. However, more specific therapeutic targets to limit axonal damage in MS need investigation and may include such integral axonal proteins such as the collapsin response mediator protein-2 (CRMP-2), a molecule which upon post-translational modification may propagate axonal degeneration in MS.
In this review, we discuss the current clinical determinants of axonal damage in MS and consider the cellular and molecular mechanisms that may initiate these neurodegenerative changes. In particular we highlight the therapeutic candidates that may formulate novel therapeutic strategies to limit axonal degeneration and EDSS during progressive MS.
Source: Acta Neuropathol Commun. 2014 Aug 27;2(1):97. [Epub ahead of print] & Pubmed PMID: 25159125 (02/09/14)
Atrophy and structural variability of the upper cervical cord in early multiple sclerosis.
Biberacher V, Boucard CC, Schmidt P, Engl C, Buck D, Berthele A, Hoshi MM, Zimmer C, Hemmer B, Mühlau M.
BACKGROUND: Despite agreement about spinal cord atrophy in progressive forms of multiple sclerosis (MS), data on clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) are conflicting.
OBJECTIVE: To determine the onset of spinal cord atrophy in the disease course of MS.
METHODS: Structural brain magnetic resonance imaging (MRI) was acquired from 267 patients with CIS (85) or RRMS (182) and 64 healthy controls (HCs). The upper cervical cord cross-sectional area (UCCA) was determined at the level of C2/C3 by a segmentation tool and adjusted for focal MS lesions. The coefficient of variation (CV) was calculated from all measurements between C2/C3 and 13 mm above as a measure of structural variability.
RESULTS: Compared to HCs (76.1±6.9 mm2), UCCA was significantly reduced in CIS patients (73.5±5.8 mm2, p=0.018) and RRMS patients (72.4±7.0 mm2, p<0.001). Structural variability was higher in patients than in HCs, particularly but not exclusively in case of focal lesions (mean CV HCs/patients without/with lesions: 2.13%/2.55%/3.32%, all p-values<0.007). UCCA and CV correlated with Expanded Disability Status Scale (EDSS) scores (r =-0.131/0.192, p=0.044/<0.001) and disease duration (r=-0.134/0.300, p=0.039/< 0.001). CV additionally correlated with hand and arm function (r=0.180, p=0.014).
CONCLUSION: In MS, cervical cord atrophy already occurs in CIS. In early stages, structural variability may be a more meaningful marker of spinal cord pathology than atrophy.
Source: Mult Scler. 2014 Aug 19. pii: 1352458514546514 & Pubmed PMID: 25139943 (27/08/14)
Cervical spinal cord volume loss is related to clinical disability progression in multiple sclerosis.
Lukas C, Knol DL, Sombekke MH, Bellenberg B, Hahn HK, Popescu V, Weier K, Radue EW, Gass A, Kappos L, Naegelin Y, Uitdehaag BM, Geurts JJ, Barkhof F, Vrenken H.
OBJECTIVE: To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort.
METHODS: A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24?months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24?months.
RESULTS: UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24?months was highest in patients with SPMS (-2.2% per year) and was significantly higher in patients with disease progression (-2.3% per year) than in stable patients (-1.2% per year; p=0.003), while annualised percentage brain volume change did not differ between subtypes (RRMS: -0.42% per year; SPMS -0.6% per year; PPMS: -0.46% per year) nor between progressive and stable patients (p=0.055). Baseline UCCA and aUCCA over 24?months were found to be relevant contributors of expanded disability status scale at month-24, while baseline UCCA as well as number of SC segments involved by lesions at baseline but not aUCCA were relevant contributors of disease progression.
CONCLUSIONS: SC MRI parameters including baseline UCCA and SC lesions were significant MRI predictors of disease progression. Progressive 24-month upper SC atrophy occurred in all MS subtypes, and was faster in patients exhibiting disease progression at month-24.
Source : J Neurol Neurosurg Psychiatry. 2014 Jun 27. pii: jnnp-2014-308021. doi: 10.1136/jnnp-2014-308021. [Epub ahead of print] & Pubmed PMID: 24973341 (30/06/14)
Researchers at VIB and Ghent University have unraveled the mechanism of necroptosis. This is a type of cell death that plays a crucial role in numerous diseases, from viral infections and loss of auditory nerve cells to multiple sclerosis, acute heart failure and organ transplantation. Having detailed knowledge of the cell death process enables a targeted search for new drugs.
Peter Vandenabeele (VIB/UGent): "The molecular mechanism of necroptosis was a complete mystery for a long time. Cells explode. But exactly how they do this was unclear. Now we have found that cells activate pore-forming molecules that make holes in the membrane. This basic research provides entirely new perspectives for the treatment of numerous chronic and acute inflammatory and degenerative diseases where necroptosis needs to be blocked. But it can also be useful to stimulate necroptosis in a controlled way, for example to circumvent the resistance of cancer cells to chemotherapy or to resensitize cancer cells to cell death."
Inflammatory reactions due to cell death
Many diseases are associated with dying cells. That is why understanding the cell death process is essential for the search for new medications. Peter Vandenabeele has many years of expertise in researching cell death, including with 'necroptosis'. In this type of cell death the cell explodes, as it were, and the cell content is released. This causes inflammatory reactions in the surrounding tissue.
Prior research shows that necroptosis occurs with a number of diseases, including viral infections, septic shock, detached retina, loss of auditory nerve cells, multiple sclerosis, acute heart failure, stroke, kidney failure and organ transplant complications. It also occurs in the presence of bad blood circulation and oxygen deficiency in the extremities or organs such as with atherosclerosis or type II diabetes.
A new therapeutic strategy: counteracting pore formation
Yves Dondelinger and Peter Vandenabeele discovered that the cellular explosion during necroptosis is paired with the formation of pores consisting of MLKL proteins. These MLKL pores are formed on the cell surface and cause the cells to absorb too much water. Because of this the cells ultimately explode. Detailed knowledge about how MLKL proteins create pores offers possibilities for developing medications for combatting or tolerating cell death by preventing or temporarily blocking this process.
Source: Medical Xpress © Medical Xpress 2011-2014 (05/06/14)
A $500,000 drug development grant from the National Multiple Sclerosis Society (NMSS) was awarded to a partnership between a multiple sclerosis research team at the Icahn School of Medicine at Mount Sinai and Karyopharm Therapeutics Inc., a clinical stage pharmaceutical company. Dr. Patrizia Casaccia, MD, PhD, Professor in the Departments of Neuroscience and Genetics and Genomics, at Icahn School of Medicine at Mount Sinai, will be the academic lead. She will test the effectiveness of a novel Karyopharm compound that can be orally administered and aimed at stopping the progressive phase of the disease. With the 14-month grant, Dr. Casaccia also hopes to gather information that will help design future clinical trials for MS treatments.
Karyopharm specializes in the synthesis of Selective Inhibitors of Nuclear Export, also known as SINE compounds. These compounds are thought to prevent the cause of irreversible damage to neurons, by blocking the early stages of neurodegeneration. Dr. Casaccia's laboratory first identified nuclear export as an important mechanism related to the initial events occurring in neurons and eventually leading to neurodegeneration. As inhibitors, these novel compounds target the nucleus in neurons, and block the accumulation of toxic substances in the axons. Axons are coated with myelin, and they can be damaged because myelin is destroyed or because they can be directly attacked by toxic factors that accumulate during the MS disease process. Neurodegenerative symptoms result from loss of myelin. Electrical signals are transmitted from the cell body of the neuron down an axon to other nerve cells, muscles, and other cells. Signal transmission slows down and progressive disability results from damage to the axons and loss of neurons, due to neurodegeneration.
Dr. Casaccia underscored the new strategy in MS drug development. "What's unique about this work is that SINE compounds target and prevent nuclear export, which is critically important for the neurodegenerative phase of the disease," she said. Preliminary experiments in Dr. Casaccia's laboratory have been encouraging. In mouse models, oral administration of the new compound to mice with paralysis of the tail and hindlimb, allowed them to walk again.
"The idea of rebuilding the nervous system and protecting it from ongoing MS damage was just a dream a few years ago," said Timothy Coetzee, Chief Advocacy, Services and Research Officer at the National MS Society. "Now, because of efforts by the research community as well as focused investments by the Society, we can see a future where people with MS will have treatments that could restore what's been lost."
In partnering with Karyopharm Therapeutics Inc., Dr. Casaccia will test these oral compounds in preclinical models and unravel their mechanism of action. The work would not be possible if the National MS Society did not invest $500,000 with Karyopharm through Fast Forward, as part of a comprehensive approach to MS research and treatment focusing on accelerating commercial development of promising research discoveries.
"We look forward to collaborating with Dr. Casaccia, who has dedicated herself to advancing research in multiple sclerosis and other important diseases," said Karyopharm Founder, Chief Scientific Officer, and President of Research and Development, Sharon Shacham, PhD, MBA.
Fred Lublin, MD, Saunders Family Professor of Neurology and the Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center also applauded this research. "Developing novel approaches to treating the neurodegenerative component of MS is critically important for our efforts at halting this disease and then reversing the damage. Existing medications for MS only aim to reduce the number of relapses. They are not restorative to the nervous system."
Source: The Mount Sinai Hospital (22/11/13)