Neuronopathic Gaucher disease: dysregulated mRNAs and miRNAs in brain pathogenesis and effects of pharmacologic chaperone treatment in a mouse model

Abstract

Defective lysosomal acid β-glucosidase (GCase) in Gaucher disease causes accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) that distress cellular functions. To study novel pathological mechanisms in neuronopathic Gaucher disease (nGD), a mouse model (4L;C*), an analogue to subacute human nGD, was investigated for global profiles of differentially expressed brain mRNAs (DEGs) and miRNAs (DEmiRs). 4L;C* mice displayed accumulation of GC and GS, activated microglial cells, reduced number of neurons and aberrant mitochondrial function in the brain followed by deterioration in motor function. DEGs and DEmiRs were characterized from sequencing of mRNA and miRNA from cerebral cortex, brain stem, midbrain and cerebellum of 4L;C* mice. Gene ontology enrichment and pathway analysis showed preferential mitochondrial dysfunction in midbrain and uniform inflammatory response and identified novel pathways, axonal guidance signaling, synaptic transmission, eIF2 and mammalian target of rapamycin (mTOR) signaling potentially involved in nGD. Similar analyses were performed with mice treated with isofagomine (IFG), a pharmacologic chaperone for GCase. IFG treatment did not alter the GS and GC accumulation significantly but attenuated the progression of the disease and altered numerous DEmiRs and target DEGs to their respective normal levels in inflammation, mitochondrial function and axonal guidance pathways, suggesting its regulation on miRNA and the associated mRNA that underlie the neurodegeneration in nGD. These analyses demonstrate that the neurodegenerative phenotype in 4L;C* mice was associated with dysregulation of brain mRNAs and miRNAs in axonal guidance, synaptic plasticity, mitochondria function, eIF2 and mTOR signaling and inflammation and provides new insights for the nGD pathological mechanism.

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations

“…Indeed most efforts to develop a pharmacological chaperone useful in clinical practice were concentrated on Gaucher disease (Figure 2). Isofagomine, an unmodified iminosugar, appeared to be very promising in stabilizing mutant glucosylceramidase [62] but did not reduce the accumulation of lipids significantly [14,63]. Besides the approaches already mentioned with alkylated or pH-sensitive molecules, another interesting option was evaluated.…”

Role of miRNAs in human disease and inborn errors of metabolism

“…Samples analyzed include lymphocytes or serum (Karatas et al 2013;L ie ta l .2014a, b;Martino et al 2015) and fibroblasts (Ozsait et al 2010;Siebert et al 2014). In other studies, mouse (Dasgupta et al 2015) or cellular models, such as knockdown cell lines or mitochondrial cybrids, have been analyzed (Meseguer et al 2015). The identified dysregulated miRNAs and/or their mRNA targets were analyzed in silico to gain insight into their contribution to disease pathogenesis.…”

“…Thus, in Niemann-Pick C, miRNA screening identified downregulated miRNAs targeting lipid metabolism genes (Ozsait et al 2010). In Gaucher mouse model brain, differentially expressed miRNAs and target mRNAs involved in inflammatory processes, mitochondrial function, and axon guidance were described (Dasgupta et al 2015). In familial Fan et al 2016) hypercholesterolemic children, miR-33a and miR-33b were found significantly upregulated in plasma, correlating with levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, apoB, C-reactive protein, and glycemia (Martino et al 2015).…”

Progress and potential of non-inhibitory small molecule chaperones for the treatment of Gaucher disease and its implications for Parkinson disease

“…On the other hand, in a PC12 cell model transfected with WT or mutant GBA1 and over-expressing α-syn, treatment of isofagomine did not significantly reduce α-syn accumulation (95). Treatment of a mouse model representative of neuronopathic GD suggested that isofagomine treatment might restore altered expression levels of miRNA and associated mRNA in processes such as inflammation, axonal guidance pathways, and mitochondrial dysfuntion which are all implicated in PD (108). In another study, patient fibroblasts homozygous for L444P treated with the sp 2 -iminosugars based inhibitory chaperone NAdBT-AIJ revealed amelioration of mitochondrial dysfunction (109).…”