Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that causes motor, sensory, and cognitive deficits. The present study characterized demyelinated lesions in the cerebral cortex of MS patients. One hundred twelve cortical lesions were identified in 110 tissue blocks from 50 MS patients. Three patterns of cortical demyelination were identified: Type I lesions were contiguous with subcortical white matter lesions; Type II lesions were small, confined to the cortex, and often perivascular; Type III lesions extended from the pial surface to cortical layer 3 or 4. Inflammation and neuronal pathology were studied in tissue from 8 and 7 patients, respectively. Compared to white matter lesions, cortical lesions contained 13 times fewer CD3-positive lymphocytes (195 vs 2,596/mm3 of tissue) and 6 times fewer CD68-positive microglia/macrophages (11,948 vs 67,956/mm3 of tissue). Transected neurites (both axons and dendrites) occurred at a density of 4,119/mm3 in active cortical lesions, 1,107/mm3 in chronic active cortical lesions, 25/mm3 in chronic inactive cortical lesions, 8/mm3 in myelinated MS cortex, and 1/mm3 in control cortex. In active and chronic active cortical lesions, activated microglia closely apposed and ensheathed apical dendrites, neurites, and neuronal perikarya. In addition, apoptotic neurons were increased significantly in demyelinated cortex compared to myelinated cortex. These data support the hypothesis that demyelination, axonal transection, dendritic transection, and apoptotic loss of neurons in the cerebral cortex contribute to neurological dysfunction in MS patients.

Premyelinating oligodendrocytes are present in chronic lesions of multiple sclerosis, so remyelination is not limited by an absence of oligodendrocyte progenitors or their failure to generate oligodendrocytes. Our findings suggest that in the chronic lesions of multiple sclerosis, the axons are not receptive for remyelination. Understanding the cellular interactions between premyelinating oligodendrocytes, axons, and the microenvironment of lesions of multiple sclerosis may lead to effective strategies for enhancing remyelination.

Objective: Degeneration of chronically demyelinated axons is a major cause of irreversible neurological disability in multiple sclerosis (MS) patients. Development of neuroprotective therapies will require elucidation of the molecular mechanisms by which neurons and axons degenerate. Methods: We report ultrastructural changes that support Ca2؉-mediated destruction of chronically demyelinated axons in MS patients. We compared expression levels of 33,000 characterized genes in postmortem motor cortex from six control and six MS brains matched for age, sex, and postmortem interval. As reduced energy production is a major contributor to Ca2؉-mediated axonal degeneration, we focused on changes in oxidative phosphorylation and inhibitory neurotransmission. Results: Compared with controls, 488 transcripts were decreased and 67 were increased (p < 0.05, 1.5-fold) in the MS cortex. Twenty-six nuclear-encoded mitochondrial genes and the functional activities of mitochondrial respiratory chain complexes I and III were decreased in the MS motor cortex. Reduced mitochondrial gene expression was specific for neurons. In addition, pre-synaptic and postsynaptic components of GABAergic neurotransmission and the density of inhibitory interneuron processes also were decreased in the MS cortex. Interpretation: Our data supports a mechanism whereby reduced ATP production in demyelinated segments of upper motor neuron axons impacts ion homeostasis, induces Ca2؉-mediated axonal degeneration, and contributes to progressive neurological disability in MS patients. Neurol 2006;59:478 -489 Rapid communication between neurons requires energy and the insulation of axons by discontinuous segments of myelin. Voltage-gated Na ϩ channels produce nerve impulses and are concentrated at the nodes of Ranvier, 1 the short unmyelinated axon segment between individual myelin internodes. The nerve impulse rapidly jumps from node to node by a process called saltatory conduction. Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) that destroys myelin, oligodendrocytes, axons, and neurons. Ann2 Pathologically, demyelination predominates during early stages of MS. Neurological disability associated with demyelinating lesions is initially reversible because of a variety of adaptive changes in the MS brain. As part of these changes, Na ϩ channels are distributed diffusely along the surface of demyelinated axons, 3 resulting in slow but effective nerve communication. This also increases the energy demands of neuronal communication and renders the demyelinated axon more susceptible to hypoxic/ischemic damage (for review, see Stys 4 ). After an initial stage (commonly 10 -15 years) of relapses and remissions (RRMS), most MS patients enter a course of irreversible and continuous neurological decline, termed secondary progressive multiple sclerosis (SPMS).2 During SPMS, new inflammatory brain lesions substantially decrease with age, 5 but neurological decline continues due in part to degeneration of chronically...

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder that affects carriers, principally males, of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene. Clinical features of FXTAS include progressive intention tremor and gait ataxia, accompanied by characteristic white matter abnormalities on MRI. The neuropathological hallmark of FXTAS is an intranuclear inclusion, present in both neurons and astrocytes throughout the CNS. Prior to the current work, the nature of the associations between inclusion loads and molecular measures (e.g. CGG repeat) was not defined. Post-mortem brain and spinal cord tissue has been examined for gross and microscopic pathology in a series of 11 FXTAS cases (males, age 67-87 years at the time of death). Quantitative counts of inclusion numbers were performed in various brain regions in both neurons and astrocytes. Inclusion counts were compared with specific molecular (CGG repeat, FMR1 mRNA level) and clinical (age of onset, age of death) parameters. In the current series, the three most prominent neuropathological characteristics are (i) significant cerebral and cerebellar white matter disease, (ii) associated astrocytic pathology with dramatically enlarged inclusion-bearing astrocytes prominent in cerebral white matter and (iii) the presence of intranuclear inclusions in both brain and spinal cord. The pattern of white matter pathology is distinct from that associated with hypertensive vascular disease and other diseases of white matter. Spongiosis was present in the middle cerebellar peduncles in seven of the eight cases in which those tissues were available for study. There is inclusion formation in cranial nerve nucleus XII and in autonomic neurons of the spinal cord. The most striking finding is the highly significant association between the number of CGG repeats and the numbers of intranuclear inclusions in both neurons and astrocytes, indicating that the CGG repeat is a powerful predictor of neurological involvement in males, both clinically (age of death) and neuropathologically (number of inclusions).

Multiple sclerosis (MS) is characterized by multifocal loss of myelin, oligodendrocytes, and axons. Potential MS therapies include enhancement of remyelination by transplantation or manipulation of endogenous oligodendrocyte progenitor cells. Characteristics of endogenous oligodendrocyte progenitors in normal human brain and in MS lesions have not been studied extensively. This report describes the distribution of cells in sections from normal adult human brain and MS lesions by using antibodies directed against NG2, an integral membrane chondroitin sulfate proteoglycan expressed by oligodendrocyte progenitor cells. Stellate-shaped NG2-positive cells were detected in the white and gray matter of normal adult human brain and appeared as abundant as, but distinct from, astrocytes, oligodendrocytes, and microglia. Stellate-shaped or elongated NG2-positive cells also were detected in chronic MS lesions. A subpopulation of the elongated NG2-positive cells expressed the putative apoptotic signaling molecule p75(NTR). TUNEL-positive cells in three active, nine chronic active, and four chronic inactive lesions, however, were p75(NTR)-negative. These studies identify cells with phenotypic markers of endogenous oligodendrocyte progenitors in the mature human CNS and suggest that functional subpopulations of NG2-positive cells exist in MS lesions. Endogenous oligodendrocyte progenitor cells may represent a viable target for future therapies intended to enhance remyelination in MS patients.

Demyelination is the hallmark of numerous neurodegenerative conditions, including multiple sclerosis. Oligodendrocyte progenitors (OPCs), which normally mature into myelin-forming oligodendrocytes, are typically present around demyelinated lesions but do not remyelinate affected axons. Here, we find that the glycosaminoglycan hyaluronan accumulates in demyelinated lesions from individuals with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. A high molecular weight (HMW) form of hyaluronan synthesized by astrocytes accumulates in chronic demyelinated lesions. This form of hyaluronan inhibits remyelination after lysolecithin-induced white matter demyelination. OPCs accrue and do not mature into myelin-forming cells in demyelinating lesions where HMW hyaluronan is present. Furthermore, the addition of HMW hyaluronan to OPC cultures reversibly inhibits progenitor-cell maturation, whereas degrading hyaluronan in astrocyte-OPC cocultures promotes oligodendrocyte maturation. HMW hyaluronan may therefore contribute substantially to remyelination failure by preventing the maturation of OPCs that are recruited to demyelinating lesions.

Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demyelination. TNFα, a proinflammatory cytokine implicated in MS, can activate necroptosis, a necrotic cell death pathway regulated by RIPK1 and RIPK3 under caspase-8 deficient conditions. Here, we demonstrate defective caspase-8 activation, as well as, activation of RIPK1, RIPK3 and MLKL, the hallmark mediators of necroptosis, in the cortical lesions of human MS pathological samples. Furthermore, we show that MS pathological samples are characterized by an increased insoluble proteome in common with other neurodegenerative diseases such as AD, PD and HD. Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNFα, and inhibition of RIPK1 protects against oligodendrocyte cell death in two animal models of MS and in culture. Our findings demonstrate that necroptosis is involved in MS and suggest that targeting RIPK1 may represent a novel therapeutic strategy for MS.

2Ј,5Ј-Oligoadenylate-dependent RNase L functions in the interferon-inducible, RNA decay pathway known as the 2-5A system. To determine the physiological roles of the 2-5A system, mice were generated with a targeted disruption of the RNase L gene. The antiviral effect of interferon α was impaired in RNase L -/-mice providing the first evidence that the 2-5A system functions as an antiviral pathway in animals. In addition, remarkably enlarged thymuses in the RNase L -/-mice resulted from a suppression of apoptosis. There was a 2-fold decrease in apoptosis in vivo in the thymuses and spleens of RNase L -/-mice. Furthermore, apoptosis was substantially suppressed in RNase L -/-thymocytes and fibroblasts treated with different apoptotic agents. These results suggest that both interferon action and apoptosis can be controlled at the level of RNA stability by RNase L. Another implication is that the 2-5A system is likely to contribute to the antiviral activity of interferon by inducing apoptosis of infected cells.