Abstract
Selective neuronal vulnerability is characteristic of most degenerative disorders of the CNS, yet mechanisms underlying this phenomenon remain poorly characterized. Many forms of cerebellar degeneration exhibit an anterior-to-posterior gradient of Purkinje cell loss including Niemann-Pick type C1 (NPC) disease, a lysosomal storage disorder characterized by progressive neurological deficits that often begin in childhood. Here, we sought to identify candidate genes underlying vulnerability of Purkinje cells in anterior cerebellar lobules using data freely available in the Allen Brain Atlas. This approach led to the identification of 16 candidate neuroprotective or susceptibility genes. We demonstrate that one candidate gene, heat shock protein beta-1 (HSPB1), promoted neuronal survival in cellular models of NPC disease through a mechanism that involved inhibition of apoptosis. Additionally, we show that over-expression of wild type HSPB1 or a phosphomimetic mutant in NPC mice slowed the progression of motor impairment and diminished cerebellar Purkinje cell loss. We confirmed the modulatory effect of Hspb1 on Purkinje cell degeneration in vivo, as knockdown by Hspb1 shRNA significantly enhanced neuron loss. These results suggest that strategies to promote HSPB1 activity may slow the rate of cerebellar degeneration in NPC disease and highlight the use of bioinformatics tools to uncover pathways leading to neuronal protection in neurodegenerative disorders.
Highlights
Selective vulnerability of specific neuronal populations is a well characterized, though often perplexing feature of many neurodegenerative diseases [1]
Mice with loss of function mutations in the Npc1 gene model many aspects of the human disease, including cerebellar degeneration that results in marked ataxia
Cerebellar Purkinje cells in mutant mice exhibit striking selective vulnerability, with neuron loss in anterior lobules and preservation in posterior lobules. As this anterior to posterior gradient is reproduced following cell autonomous deletion of Npc1 and is observed in other forms of cerebellar degeneration, we hypothesized that it is mediated by differential gene expression
Summary
Selective vulnerability of specific neuronal populations is a well characterized, though often perplexing feature of many neurodegenerative diseases [1]. Diseases displaying the classic anterior-to-posterior gradient may arise from genetic mutations, including spinocerebellar ataxias type 1 [4] and 6 [5], late infantile neuronal ceroid lipofuscinosis [6], saposin C deficiency, a rare cause of Gaucher Disease [7], ataxia telangiectasia [8], and Niemann-Pick disease types A/B [9] and C [10]; sporadic disorders, including multiple system atrophy [11] and chronic epilepsy [12]; toxins, including alcohol [13], cytosine arabinoside [14], methotrexate [15]; hypoxia/ischemia [16, 17]; paraneoplastic syndromes [18]; and even normal aging [19] This pattern is seen in many spontaneous mouse mutants, including pcd [20], leaner [21], toppler [22], robotic [23], shaker [24], and lurcher [25]; or targeted mutants, such as saposin D knockout [26], prion protein knockout [27], and over-expression of the prion protein related gene doppel [28]. We hypothesize that the identification of pathways responsible for this phenomenon will yield therapeutic targets broadly applicable to this large class of cerebellar disorders
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