Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0153640 (Cerebellum)
1,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The devastating nature and lack of effective treatments associated with neurodegenerative diseases have stimulated a world-wide search for the elucidation of their molecular basis to which mouse models have made a major contribution. In combination with transgenic and knockout technologies, large-scale mouse mutagenesis is a powerful approach for the identification of new genes and associated signalling pathways controlling neuronal cell death and survival. Here we review the characterization of the robotic mouse, a novel model of autosomal dominant cerebellar ataxia isolated from an ENU-mutagenesis programme, which develops adult-onset region-specific Purkinje cell loss and cataracts, and displays defects in early T-cell maturation and general growth retardation. The mutated protein, Af4, is a member of the AF4/LAF4/FMR2 (ALF) family of putative transcription factors previously implicated in childhood leukaemia and FRAXE mental retardation. The mutation, which lies in a highly conserved region among the ALF family members, significantly reduces the binding affinity of Af4 to the E3 ubiquitin-ligase Siah-1a, isolated with Siah-2 as interacting proteins in the brain. This leads to a markedly slower turnover of mutant Af4 by the ubiquitin-proteasome pathway and consequently to its abnormal accumulation in the robotic mouse. Importantly, the conservation of the Siah-binding domain of Af4 in all other family members reveals that Siah-mediated proteasomal degradation is a common regulatory mechanism that controls the levels, and thereby the function, of the ALF family. The robotic mouse represents a unique model in which to study the newly revealed role of Af4 in the maintenance of vital functions of Purkinje cells in the cerebellum and further the understanding of its implication in lymphopoeisis.
Cerebellum 2005
PMID:The robotic mouse: unravelling the function of AF4 in the cerebellum. 1632 81

The ubiquitin-proteasome system (UPS) is one of the major mechanisms for protein breakdown in cells, targeting proteins for degradation by enzymatically conjugating them to ubiquitin molecules. Intracellular accumulation of ubiquitin-B⁺¹ (UBB⁺¹), a frameshift mutant of ubiquitin-B, is indicative of a dysfunctional UPS and has been implicated in several disorders, including neurodegenerative disease. UBB⁺¹-expressing transgenic mice display widespread labeling for UBB⁺¹ in brain and exhibit behavioral deficits. Here, we show that UBB⁺¹ is specifically expressed in a subset of parasagittal stripes of Purkinje cells in the cerebellar cortex of a UBB⁺¹-expressing mouse model. This expression pattern is reminiscent of that of the constitutively expressed Purkinje cell antigen HSP25, a small heat shock protein with neuroprotective properties.
Cerebellum 2017 06
PMID:Selective Transgenic Expression of Mutant Ubiquitin in Purkinje Cell Stripes in the Cerebellum. 2796 98

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