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Identification of Novel Pathways Associated with Patterned International Journal of Molecular Sciences Article Identification of Novel Pathways Associated with Patterned Cerebellar Purkinje Neuron Degeneration in Niemann-Pick Disease, Type C1 Kyle B. Martin 1, Ian M. Williams 1, Celine V. Cluzeau 1, Antony Cougnoux 1, Ryan K. Dale 2, James R. Iben 3, Niamh X. Cawley 1, Christopher A. Wassif 1 and Forbes D. Porter 1,* 1 Section on Molecular Dysmorphology, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA; [email protected] (K.B.M.); [email protected] (I.M.W.); [email protected] (C.V.C.); [email protected] (A.C.); [email protected] (N.X.C.); [email protected] (C.A.W.) 2 Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA; [email protected] 3 Molecular Genomics Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-301-435-4432 Received: 7 December 2019; Accepted: 25 December 2019; Published: 31 December 2019 Abstract: Niemann-Pick disease, type C1 (NPC1) is a lysosomal disease characterized by progressive cerebellar ataxia. In NPC1, a defect in cholesterol transport leads to endolysosomal storage of cholesterol and decreased cholesterol bioavailability. Purkinje neurons are sensitive to the loss of NPC1 function. However, degeneration of Purkinje neurons is not uniform. They are typically lost in an anterior-to-posterior gradient with neurons in lobule X being resistant to neurodegeneration. To gain mechanistic insight into factors that protect or potentiate Purkinje neuron loss, we compared RNA expression in cerebellar lobules III, VI, and X from control and mutant mice. An unexpected finding was that the gene expression differences between lobules III/VI and X were more pronounced than those observed between mutant and control mice. Functional analysis of genes with anterior to posterior gene expression differences revealed an enrichment of genes related to neuronal cell survival within the posterior cerebellum. This finding is consistent with the observation, in multiple diseases, that posterior Purkinje neurons are, in general, resistant to neurodegeneration. To our knowledge, this is the first study to evaluate anterior to posterior transcriptome-wide changes in gene expression in the cerebellum. Our data can be used to not only explore potential pathological mechanisms in NPC1, but also to further understand cerebellar biology. Keywords: Niemann–Pick disease; type C1; NPC1; cerebellum; neurodegeneration; Purkinje neurons; RNA-seq; WGCNA 1. Introduction Niemann–Pick disease, type C (NPC) is a rare autosomal recessive disorder characterized by accumulation of unesterified cholesterol and glycosphingolipids within the endo-lysosomal system. Although the age of onset and clinical manifestations are heterogenous, NPC patients may present with neonatal cholestasis or hepatosplenomegaly. These visceral signs often precede the onset of progressive neurological disorders, which include vertical supranuclear gaze palsy, dementia, and cerebellar ataxia [1,2]. NPC is caused by mutations in either NPC1 or NPC2, which encode a lysosomal Int. J. Mol. Sci. 2020, 21, 292; doi:10.3390/ijms21010292 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 292 2 of 26 transmembrane protein and a small soluble lysosomal protein, respectively [2,3]. Together, the NPC1 and NPC2 proteins function to facilitate the efflux of cholesterol from the late endosome-lysosome compartment, as mutations in either gene leads to the accumulation of unesterified cholesterol, glycosphingolipids, and additional lipids within this compartment [2,4,5]. However, the pathological mechanisms by which these mutations lead to progressive neurodegeneration remains unclear. A common neurological complication observed in NPC1 patients is cerebellar ataxia [6]. The cerebellum is a highly organized and conserved structure that, in mammals and birds, is divided into ten distinct lobules by shallow fissures. Although each lobule has a distinct form, each is comprised of three layers. The center layer is the Purkinje neuron layer, which derives its name from the monolayer of Purkinje soma that aligns within each lobule. The Purkinje neurons extend elaborate dendrites into the outermost molecular layer, where they form excitatory synapses with climbing fibers that originate from the inferior olivary nucleus. The innermost granule cell layer is mainly comprised of granule cells, which are a densely packed neuronal cell type. Granule cells account for the largest neuronal population within the brain. In the cerebellum, granule cells function to transmit excitatory input from mossy fibers to the dendrites of the Purkinje neurons through their long axonal projections, known as parallel fibers. Hence, synaptic inputs from granule cells and the climbing fibers are integrated by the Purkinje neurons before being projected down their axons, where they make inhibitory synaptic contact with cerebellar nuclei at the base of the cerebellum. Therefore, Purkinje neurons represent the sole output of the cerebellum, as they integrate all cerebellar inputs before projecting to their target neurons [7]. Although the structure of the cerebellar cortex is consistent throughout all lobules, distinct patterns of gene expression generate highly reproducible transverse zones within the cerebellum that can further be divided into parasagittal stripes [8,9]. The most common marker of these zones and stripes is zebrin II, which has been identified as the glycolytic enzyme, aldolase C [8,10]. Zebrin II is a Purkinje neuron specific marker that is expressed in a distinct subset of aligned Purkinje neurons, thus resulting in an alternating array of zebrin II-positive and zebrin II-negative parasagittal stripes [11]. Furthermore, these stripes form larger domains that comprise four separate transverse zones of the cerebellum: the striped anterior zone (lobules I–V), the homogeneously zebrin II-positive central zone (lobules VI–VII), the striped posterior zone (lobules VIII–dorsal IX), and the uniformly zebrin II-positive nodular zone (ventral lobule IX–X) [9,12]. These unique gene expression patterns also give rise to functional differences, as many cerebellar disorders resulting in Purkinje neuron death are restricted to specific zones or parasagittal stripes [13]. Purkinje neurons within the zebrin II-negative stripes are more susceptible to cell death, resulting in an anterior-to-posterior gradient of neurodegeneration. This pattern is observed in multiple spontaneous mouse models, such as the Purkinje cell degeneration (Nna1pcd)[14], tottering (Cacna1atg)[15], and lurcher (Grid2lc)[16] mice, or in response to numerous exogenous toxins, such as ibogaine [17], cytosine arabinoside [18], methotrexate [19], and alcohol [20–22]. Similar anterior-to-posterior Purkinje neuron death patterns are observed in multiple genetic disorders, including those for multiple forms of the spinocerebellar ataxias [23–25], Menkes syndrome [26,27], Niemann–Pick disease type A/B[28], and Niemann–Pick disease type m1N / C1 [29]. For NPC1, studies utilizing BALB/cNctr-Npc1 /J(Npc1− −) mice have demonstrated that the Purkinje neurons undergo a patterned cell death that initially affects the zebrin II-negative Purkinje neurons starting at approximately postnatal day 40 [30]. As the disease progresses, additional zebrin II-positive Purkinje neurons throughout lobules I–IX are also lost. This progression continues until the animal succumbs to the disease, usually around postnatal day 70 to 90, at which time the only Purkinje neurons that remain are those zebrin II-positive cells of the ventral portion of lobule IX and the entire lobule X [31]. This spatiotemporal patterned cell death occurs despite the consistent presence of unesterified cholesterol accumulation and neuroinflammation throughout all the cerebellar lobules [32,33]. Int. J. Mol. Sci. 2020, 21, 292 3 of 26 To gain mechanistic insight into factors that would either protect Purkinje neurons or potentiate their degeneration, we evaluated spatial cerebellar RNA expression patterns. Cerebellar lobules III, VI, +/+ / and X were individually microdissected from asymptomatic 4.5-week-old Npc1 and Npc1− − mice. RNA-sequencing was performed and weighted gene co-expression network analysis (WGCNA) [34] was utilized to observe any intrinsic, or NPC1-specific, differences in gene expression that may / contribute to the survival of Purkinje neurons in lobule X of Npc1− − mice. 2. Results 2.1. Immunohistochemistry and RNA-Sequencing / Immunohistochemistry of calbindin staining in the cerebellum of Npc1− − mice confirmed the temporal and lobule specific loss of Purkinje neurons with disease progression when compared to Npc1+/+ littermates, which have a consistent Purkinje neuron density throughout their lifespan / (Figure1A). At 4.5 weeks of age, the staining pattern of Npc1− − Purkinje neurons demonstrated no / signs of neurodegeneration, consistent with a pre-symptomatic state of the Npc1− − mice (Figure1B). At seven weeks of age, however, the Purkinje neurons of the anterior cerebellar transverse zone (lobules I–V) have mostly degenerated, leaving
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