Justyna R. Sarna

Patterned Purkinje cell death in the cerebellum.

The object of this review is to assemble much of the literature concerning Purkinje cell death in cerebellar pathology and to relate this to what is now known about the complex topography of the cerebellar cortex. A brief introduction to Purkinje cells, and their regionalization is provided, and then the data on Purkinje cell death in mouse models and, where appropriate, their human counterparts, have been arranged according to several broad categories--naturally-occurring and targeted mutations leading to Purkinje cell death, Purkinje cell death due to toxins, Purkinje cell death in ischemia, Purkinje cell death in infection and in inherited disorders, etc. The data reveal that cerebellar Purkinje cell death is much more topographically complex than is usually appreciated.

Patterned Purkinje cell degeneration in mouse models of Niemann‐Pick type C disease

Niemann Pick disease type C1 (NPC1) is an inherited, autosomal recessive, lipid‐storage disorder with major neurological involvement. Purkinje cell death is a prominent feature of the neuropathology of NPC. We have investigated Purkinje cell death in two murine models of NPC1, BALB/c npcnih and C57BLKS/J spm. In both cases, extensive Purkinje cell death was found in the cerebellum. The pattern of Purkinje cell death is complex. First, zebrin II‐negative Purkinje cells disappear, to leave survivors aligned in stripes that closely resemble the pattern revealed by using zebrin II immunocytochemistry. Subsequently, as the disease progresses, additional Purkinje cells die. At the terminal stages of the disease, the surviving Purkinje cells are concentrated in lobules IX and X of the posterior lobe vermis. Purkinje cell degeneration is accompanied by the ectopic expression of tyrosine hydroxylase and the small heat shock protein HSP25, both associated preferentially with the surviving cells. The pattern of cell death thus reflects the fundamental compartmentation of the cerebellum into zones and stripes. J. Comp. Neurol. 456:279–291, 2003.

Complementary stripes of phospholipase Cβ3 and Cβ4 expression by Purkinje cell subsets in the mouse cerebellum

Transverse boundaries divide the cerebellar cortex into four transverse zones, and within each zone the cortex is further subdivided into a symmetrical array of parasagittal stripes. Several molecules believed to mediate long‐term depression at the parallel fiber–Purkinje cell synapse are known to be expressed in stripes. We have therefore explored the distributions of phospholipase Cβ3 and phospholipase Cβ4, key components in the transduction of type 1 metabotropic glutamate receptor‐mediated responses. The data reveal that both phospholipase Cβ isotypes are expressed strongly in the mouse cerebellum in subsets of Purkinje cells. The two distributions are distinct and largely nonoverlapping. The pattern of phospholipase Cβ3 expression is unique, revealing stripes in three of the four transverse zones and a uniform distribution in the fourth. In contrast, phospholipase Cβ4 appears to be confined largely to the Purkinje cells that are phospholipase Cβ3‐negative. PLCβ3 is restricted to the zebrin II‐immunopositive Purkinje cell subset. Not all zebrin II‐immunoreactive Purkinje cells express PLCβ3: in lobules IX and X it is restricted to that zebrin II‐immunopositive subset that also expresses the small heat shock protein HSP25. PLCβ4 expression is restricted to, and coextensive with, the zebrin II‐immunonegative Purkinje cell subset. These nonoverlapping expression patterns suggest that long‐term depression may be manifested differently between cerebellar modules. J. Comp. Neurol. 496:303–313, 2006.

Impairment of pronation, supination, and body co-ordination in reach-to-grasp tasks in human Parkinson's disease (PD) reveals homology to deficits in animal models.

Animal (monkey, rat, mouse) models are widely used to investigate degenerative processes and potential therapeutic treatments for human Parkinsons disease (PD). One task that has proved useful in these investigations is a reach-to-grasp task (skilled reaching) in which an animal reaches for a piece of food that it then consumes. Rats with extensive unilateral Dopamine depletions are impaired in using the contralateral limb. The qualitative features of posture, lifting and advancing the limb, pronating the paw to grasp food, and in withdrawing and supinating the paw to place the food in the mouth are impaired, as is reaching success. Humans with PD are often described as having poor manual dexterity that worsens as the disease progresses. As there have been no detailed comparisons of reaching movements in the animal models and in PD subjects, the following descriptive analysis was performed. Ten subjects with PD, eight age matched controls and 14 young normal subjects were studied as they used a natural movement of reaching for a small piece of food that they then placed in the mouth to eat. The reaching movements were described using Eshkol-Wachman Movement Notation (EWMN), supplemented with kinematic analyses. From this description, a 21-point rating scale was devised to describe the component movements of the reach. Movements included: orienting the head and eyes to the target, adjusting posture, lifting the hand, shaping and aiming the digits to the target, pronating the hand to grasping the food with a pincer grip, lifting and supinating the hand to transporting the food to the mouth, and further supinating the hand and opening the digits to place food in the mouth, and finally returning the hand to the starting position. Analysis indicated that most aspects of the reaching movements of the PD subjects were significantly different relative to both young control subjects and old control subjects. As compared to the control groups, postural and reaching components of the movements were fragmented, movements were achieved using more proximal segments of the body, and rotatory movements of the hand were limited. The PD subjects did use a pincer grasp to obtain the food, but the grasp was less independent of other digit movements than was observed in the control subjects. These results are discussed in terms of a homology to impairments displayed animal models of PD.

Patterned cerebellar Purkinje cell death in a transgenic mouse model of Niemann Pick type A/B disease

Niemann Pick disease is a family of autosomal recessive disorders characterized by cholesterol accumulation. The most common type is Niemann Pick type A/B (NPA/B), resulting from deficient acid sphingomyelinase activity, which leads to sphingomyelin and cholesterol accumulation. The neuropathology of NPA/B includes widespread neuronal degeneration. An acid sphingomyelinase knockout mouse model of NPA/B (ASMKO) has been developed by the targeted deletion of the acid sphingomyelinase gene. When cerebellar morphology was examined in the ASMKO mouse at postnatal day 60 (P60), a dramatic pattern of longitudinal stripes was revealed in which roughly half the Purkinje cells had died, leaving a highly stereotyped, bilaterally symmetrical array of stripes. Antizebrin II immunocytochemistry revealed that the absent Purkinje cells corresponded exactly to the zebrin II‐negative subset, leaving the zebrin II‐positive subset apparently intact. By P120, some of the zebrin II‐positive Purkinje cells had also been eliminated from the posterior vermis and hemispheres. By P180, all Purkinje cells had been lost from the anterior lobe. Finally at P240, almost all Purkinje cells had disappeared to leave a stereotyped distribution in lobules VI, IX–X and the flocculus and paraflocculus. The temporal pattern of Purkinje cell death demonstrates differential susceptibility of morphologically identical cells that appear to be linked to their molecular phenotypes.

Compartmentation of the mouse cerebellar cortex by sphingosine kinase.

Classic cerebellar anatomy is based on the characteristic array of lobes and lobules. However, there is substantial evidence to suggest that more fundamental architecture is built around arrays of parasagittal stripes, which encompass both the inputs and outputs of the Purkinje cells (PCs). Sphingosine kinase (SPHK) is an enzyme that converts sphingosine (Sph) into sphingosine‐1‐phosphate (S1P). Recent reports have indicated that ceramide, Sph, and S1P play a role in cell survival, growth, and differentiation in several cell types, including neurons. In this study, we examined the localization of SPHK in the mouse cerebellum by using immunohistochemistry. Anti‐SPHK immunoreactivity appeared in the cerebellar molecular layer and the PC membranes. The staining pattern is striped. In the molecular layer, the staining pattern probably reflects dendritic spines and dendrites. By electron microscopy, peroxidase reaction product was deposited within dendrites especially along the plasma membranes near spines. Seen at higher magnification, the staining was in and near the postsynaptic complexes. By double immunostaining, the striped pattern of SPHK expression was shown to be identical to that revealed by anti‐zebrin II, although the subcellular distribution within PCs is not. This is the first demonstration of the cerebellar compartmentation of an enzyme related to lipid metabolism, and as such, it provides an insight into the roles of SPHK and formation of S1P. The selective expression of SPHK in the zebrin II‐immunoreactive PCs may explain their resistance to cell death when ceramide metabolism is disrupted, as in the acid sphingomyelinase knockout model of Niemann‐Pick type A/B disease. J. Comp. Neurol. 469:119–127, 2004.

Heat shock protein 25 expression and preferential Purkinje cell survival in the lurcher mutant mouse cerebellum.

The spatial organization of the mouse cerebellum into transverse zones and parasagittal stripes is reflected during the temporal progression of Purkinje cell death in the Lurcher mutant mouse (+/Lc). Neurodegeneration in the +/Lc mutant is apparent by the second postnatal week and is initially seen in all four transverse zones: the anterior (lobules I–V), central (lobules VI, VII), posterior (lobules VIII, dorsal IX), and nodular (ventral lobule IX and lobule X) zone. However, from postnatal day (P)25–P36, Purkinje cell loss proceeds more rapidly in the anterior zone, followed by the posterior and central zones, and is significantly delayed in the nodular zone. Coronal sections through the +/Lc cerebellum reveal that surviving Purkinje cells are restricted to the paraflocculus/flocculus and the nodular zone and could be detected as late as P146 (∼5 months). Within this region, the pattern of preferentially surviving calbindin‐immunoreactive Purkinje cells reflects the expression of the constitutively expressed small heat shock protein HSP25 in the wild‐type cerebellum. Although the role of constitutively expressed HSP25 in the wild‐type cerebellum is not clear, it appears to play a neuroprotective role in the flocculonodular region of the +/Lc mutant cerebellum as the percentage of surviving Purkinje cells that are HSP25‐immunopositive significantly increases over time. J. Comp. Neurol. 518:1892–1907, 2010.

The Neuroplastin Adhesion Molecules Are Accessory Proteins That Chaperone the Monocarboxylate Transporter MCT2 to the Neuronal Cell Surface

Background The neuroplastins np65 and np55 are two synapse-enriched immunoglobulin (Ig) superfamily adhesion molecules that contain 3 and 2 Ig domains respectively. Np65 is implicated in long term, activity dependent synaptic plasticity, including LTP. Np65 regulates the surface expression of GluR1 receptor subunits and the localisation of GABAA receptor subtypes in hippocampal neurones. The brain is dependent not only on glucose but on monocarboxylates as sources of energy. The. monocarboxylate transporters (MCTs) 1–4 are responsible for the rapid proton-linked translocation of monocarboxylates including pyruvate and lactate across the plasma membrane and require association with either embigin or basigin, proteins closely related to neuroplastin, for plasma membrane expression and activity. MCT2 plays a key role in providing lactate as an energy source to neurons. Methodology/Findings Here we use co-transfection of neuroplastins and monocarboxylate transporters into COS-7 cells to demonstrate that neuroplastins can act as ancillary proteins for MCT2. We also show that Xenopus laevis oocytes contain endogenous neuroplastin and its knockdown with antisense RNA reduces the surface expression of MCT2 and associated lactate transport. Immunocytochemical studies show that MCT2 and the neuroplastins are co-localised in rat cerebellum. Strikingly neuroplastin and MCT2 are enriched in the same parasagittal zebrin II-negative stripes. Conclusions These data strongly suggest that neuroplastins act as key ancillary proteins for MCT2 cell surface localisation and activity in some neuronal populations, thus playing an important role in facilitating the uptake of lactate for use as a respiratory fuel.

Patterned Purkinje cell loss in the ataxic sticky mouse

The ataxic sticky (sti/sti) mouse is a spontaneous autosomal recessive mutant resulting from a disruption in the editing domain of the alanyl‐tRNA synthetase (Aars) gene. The sticky phenotype is characterized by a small body size, a characteristic unkempt coat and neurological manifestations including marked tremor and ataxia starting at 6 weeks of age. The present study was undertaken to examine the spatiotemporal features of Purkinje cell degeneration in the sticky mouse. Purkinje cell loss was found to be both progressive and patterned, with vermal lobules VI, IX and X, crus 1 of the hemisphere, and the flocculus and paraflocculus being differentially resistant to degeneration. The pattern of Purkinje cell degeneration in sticky is not random – in general, the sphingosine kinase 1a‐immunonegative Purkinje cell subset is preferentially susceptible to early cell death. In addition, zebrin II/aldolase C expression in the sticky cerebellum is profoundly downregulated, whereas the heat‐shock protein 25 is both ectopically expressed in some scattered Purkinje cells and downregulated in other Purkinje cells in which it is normally expressed constitutively. Compared with many mouse mutants with patterned Purkinje cell death, in which successive stripes of cell loss are very clear, Purkinje cell loss in sticky shows a less clear‐cut pattern between different Purkinje cell subtypes, with the result that preferential survival is less dramatic. This may represent a secondary consequence of the downregulation of zebrin II expression.

Reversible cerebellar syndrome caused by metronidazole

A 54-year-old man presented with a 3-day history of difficulty speaking and an unsteady gait after having a generalized tonic-clonic seizure. He had been taking oral metronidazole for bronchiectasis for 2 months before presentation (estimated cumulative dose of about 60 g). His medical history