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Axonal degeneration is a prominent feature of amyotrophic lateral sclerosis (ALS) both in lower motor nerves as well as descending white matter axons in the spinal cord of human patients. Although the pathology of lower motor axonal degeneration has been described in both human ALS and related transgenic animal models, few studies have examined the pathological features of descending axon degeneration, particularly in mouse models of ALS. We have examined the degeneration of white matter tracts in the G93A mutant superoxide dismutase-1 (mSOD1+) mouse spinal cord white matter from 12 weeks of age to end-stage disease. In a G93A mSOD1 mouse model where green fluorescent protein was expressed in neurons (mSOD1+/GFP+), degeneration of white matter tracts was present from the ventral to dorsolateral funiculi. This pattern of axonal pathology occurred from 16 weeks of age. However, the dorsal funiculus, the site of the major corticospinal tract in mice, showed relatively less degeneration. Immunohistochemical analysis demonstrated that the neurofilament light chain (NFL) and neuronal intermediate filament protein alpha-internexin accumulated in axon swellings in the spinal white matter. Increased levels of alpha-internexin protein, in mSOD1+ mouse spinal cord tissue, were demonstrated by Western blotting. In contrast, degenerating axons did not show obvious accumulations of neurofilament medium and heavy chain proteins (NFM and NFH). These data suggest that white matter degeneration in this mouse model of ALS is widespread and involves a specific molecular signature, particularly the accumulation of NFL and alpha-internexin proteins., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We examined neurodegeneration in spinal cord (SC) and role of such extra-nigral degeneration in MPTP-induced experimental parkinsonism in C57BL/6N mice. HPLC-photodiode array analysis confirmed presence of the active neurotoxin MPP+ in SC after single injection of MPTP (25 mg/kg, i.p.). Mitochondrial enzyme monoamine oxidase-B (MAO-B) responsible for in vivo conversion of MPTP to MPP+ was inhibited in SC by pre-treatment with l-deprenyl, a specific inhibitor of MAO-B. Besides in vitro conversion of MPTP to MPP+ occurred by SC mitochondrial preparation, which was inhibited by l-deprenyl implicating SC as a specific target of MPTP-neurotoxicity. Double immunofluorescent labeling and spectrofluorimetric assay via kynuramine oxidation showed MAO-B expression and activity in SC neurons. Localization of dopamine transporter immunoreactivity in SC along with specific uptake of (3)H-MPP+ by SC synaptosomal preparation further confirmed SC as target of MPTP-neurotoxicity. Compared with control, increased neuronal death on the seventh day in SC of mice injected with MPTP (2 x 25 mg/kg, at 6 h interval) strongly suggested SC degeneration in pre-symptomatic phase of MPTP-induced experimental parkinsonism. Such extra-nigral neurodegeneration in Parkinson's disease indicated novel molecular mechanism preceding nigrostriatal degeneration and suggested designing broad therapeutic intervention for this complex movement disorder.

Presenilins (PS) play a central role in gamma-secretase-mediated processing of beta-amyloid precursor protein (APP) and numerous type I transmembrane proteins. Expression of mutant PS1 variants causes familial forms of Alzheimer's disease (FAD). In cultured mammalian cells that express FAD-linked PS1 variants, the intracellular trafficking of several type 1 membrane proteins is altered. We now report that the anterograde fast axonal transport (FAT) of APP and Trk receptors is impaired in the sciatic nerves of transgenic mice expressing two independent FAD-linked PS1 variants. Furthermore, FAD-linked PS1 mice exhibit a significant increase in phosphorylation of the cytoskeletal proteins tau and neurofilaments in the spinal cord. Reductions in FAT and phosphorylation abnormalities correlated with motor neuron functional deficits. Together, our data suggests that defects in anterograde FAT may underlie FAD-linked PS1-mediated neurodegeneration through a mechanism involving impairments in neurotrophin signaling and synaptic dysfunction.

Exposure to environmental toxins increases the risk of neurodegenerative diseases including Parkinson's disease (PD). Rotenone is a neurotoxin that has been used to induce experimental Parkinsonism in rats. We used the rotenone model of experimental Parkinsonism to explore a novel aspect of extra-nigral degeneration, the neurodegeneration of spinal cord (SC), in PD. Rotenone administration to male Lewis rats caused significant neuronal cell death in cervical and lumbar SC as compared with control animals. Dying neurons were motoneurons as identified by double immunofluorescent labeling for terminal deoxynucleotidyl transferase, recombinant-mediated dUTP nick-end labeling-positive (TUNEL(+)) cells and choline acetyltransferase (ChAT)-immunoreactivity. Neuronal death was accompanied by abundant astrogliosis and microgliosis as evidenced from glial fibrillary acidic protein (GFAP)-immunoreactivity and OX-42-immunoreactivity, respectively, implicating an inflammatory component during neurodegeneration in SC. However, the integrity of the white matter in SC was not affected by rotenone administration as evidenced from the non co-localization of any TUNEL(+) cells with GFAP-immunoreactivity and myelin basic protein (MBP)-immunoreactivity, the selective markers for astrocytes and oligodendrocytes, respectively. Increased activities of 76 kD active m-calpain and 17/19 kD active caspase-3 further demonstrated involvement of these enzymes in cell death in SC. The finding of ChAT(+) cell death also suggested degeneration of SC motoneurons in rotenone-induced experimental Parkinsonism. Thus, this is the first report of its kind in which the selective vulnerability of a putative parkinsonian target outside of nigrostriatal system has been tested using an environmental toxin to understand the pathophysiology of PD. Moreover, rotenone-induced degeneration of SC motoneuron in this model of experimental Parkinsonism progressed with upregulation of calpain and caspase-3.

The central role of T cells in inflammatory reactions of the central nervous system (CNS) is well documented. However, there is little information about the few T cells found within the noninflamed CNS. In particular, the contribution of CD4+ and CD8+ T cells to the lymphocyte pool infiltrating the intact CNS, the location of these cells in CNS white and gray matter, and changes in the cellular composition of T-cell infiltrates coinciding with degeneration are primarily undefined. To address these points, we studied T cells in the intact and degenerative rat spinal cord. In the intact spinal cord, T cells were preferentially located within the gray matter. CD8+ T cells were more numerous than CD4+ lymphocytes. In cases of neuroaxonal degeneration or myelin degeneration/oligodendrocyte death, T cells were predominantly seen in areas of degeneration and were present in increased numbers. These effects were more pronounced for the CD4+ than for the CD8+ T-cell subset. Collectively, these data provide evidence for a clear cellular and compartmental bias in T-cell infiltration of the intact and degenerative spinal cord. This could indicate that CD4+ and CD8+ T cells might fulfill complementary roles in the intact and the diseased organ.

Over the last few years we have reproduced all of the key morphological and biochemical features of human subacute combined degeneration in the central nervous system and peripheral nervous system of rats made cobalamin-deficient by means of total gastrectomy or a chronic cobalamin-deficient diet. We have also recently clarified the pathogenesis of experimental subacute combined degeneration induced in the rat by cobalamin deprivation. The results of our studies strongly support the notion that cobalamin plays a pivotal role in regulating the balance of the network of cytokines and growth factors in the central nervous system of the rat. We have demonstrated that cobalamin tightly regulates the central nervous system synthesis and/or the cerebrospinal fluid level of two cytokines, tumor necrosis factor-alpha and interleukin-6, and a growth factor, epidermal growth factor. Of these neuroactive agents, one, tumor necrosis factor-alpha, is neurotoxic, whereas the others are neurotrophic. Therefore, it becomes clear that cobalamin-deficient central neuropathy is caused not by the withdrawal of the vitamin, but reflects a locally increased production of neurotoxic agents, combined with the locally decreased production of neurotrophic agents.

Tissues from non-degenerated tissue of 18 patients were assayed for glycine concentration in grey and white matter in the thoracic, cervical and lumbar regions. Confirming earlier results, glycine concentration was found to be maximal in the grey matter of the lumbar segments of the lateral column. Analysis of tissue from 11 human spinal cords showing unilateral Wallerian degeneration, 4 cords with amyotrophic sclerosis and 4 cords with bilateral Wallerian degeneration failed to show statistically significant differences when compared with control values. The results argue against a supraspinal origin of glycine and suggest that glycine levels are regulated locally or at a segmental level in the spinal cord in man.

A simplified classification of the spinocerebellar degenerations is proposed. Axonal ataxias include Friedreich's ataxia and other conditions involving, primarily, neurons with very long axons. Multiple system degenerations include the various olivopontocerebellar atrophies and related disorders. Ataxic encephalopathies are diffuse diseases of the nervous system in which ataxia is a prominent clinical feature. Several lines of data suggest that mitochondrial damage is a common mechanism in the spinocerebellar degenerations. Reasonable pathophysiological mechanisms can be invoked, linking mitochondrial damage to the observed pathologies (including the many cases of intermediate on variant forms).

In 28 patients suffering from subacute combined degeneration of the spinal cord, vitamin B12 metabolism was investigated. Two postulates, proving vitamin B12 deficiency and excluding another cause for the clinical symptoms, have to be fulfilled. Two patients had no disturbance in their vitamin B12 metabolism. Seven patients had a distinct vitamin B12 deficiency. In the remaining 19 patients we found a mild vitamin B12 deficiency. Of these patients, 5 had had a subtotal gastrectomy, one had had a low absorption of vitamin B12, and 13 patients we could not find a distinct cause for the vitamin B12 deficiency. It is not impossible that nutritional habits can be hold responsible for this deficiency. The question whether these 13 patients should be treated with vitamin B12 for the rest of their lives is difficult to answer. It is a conditio sine qua non that in the patients with S.C.D. the vitamin B12 metabolism is examined circumstantially. By so doing, it may be possible to detect, in cases with minor clinical signs and symptoms of S.C.D., the cause of their illness.