Update on canine filaggrin: a review.

Human filaggrin (FLG) plays a key role in epidermal barrier function, and loss-of-function mutations of its gene are primarily responsible for the development of human atopic dermatitis (AD). FLG expression is also reduced in the epidermis of atopic patients, due to the transcriptional effect of Th2 type cytokines. Canine atopic dermatitis (CAD) is a prevalent skin disease that shares many clinical and pathogenic features with its human homologue. The aim of this review is discuss current knowledge on canine filaggrin (Flg) in both healthy and atopic dogs, as compared to the human protein. Although the molecular structures of the two proteins, as deduced from the sequences of their gene, are different, their sites of expression and their proteolytic processing in the normal epidermis are similar. Concerning the expression of Flg in CAD, conflicting results have been published at the mRNA level and little accurate information is available at the protein level. It derives from a large precursor, named profilaggrin (proFLG), formed by several FLG units and stored in keratohyalin granules of the stratum granulosum. Canine and human proFLG sequences display little amino acid similarity (33% as shown using the Basic Local Alignment Search Tool (BLAST)) except at the level of the S100 homologous part of the N-terminus (75%). Genetic studies in the dog are at an early stage and are limited by the variety of breeds and the small number of cases included. Many questions remain unanswered about the involvement of Flg in CAD pathogenesis.

A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration.

Several neurodegenerative diseases are typified by intraneuronal alpha-synuclein deposits, synaptic dysfunction, and dementia. While even modest alpha-synuclein elevations can be pathologic, the precise cascade of events induced by excessive alpha-synuclein and eventually culminating in synaptotoxicity is unclear. To elucidate this, we developed a quantitative model system to evaluate evolving alpha-synuclein-induced pathologic events with high spatial and temporal resolution, using cultured neurons from brains of transgenic mice overexpressing fluorescent-human-alpha-synuclein. Transgenic alpha-synuclein was pathologically altered over time and overexpressing neurons showed striking neurotransmitter release deficits and enlarged synaptic vesicles; a phenotype reminiscent of previous animal models lacking critical presynaptic proteins. Indeed, several endogenous presynaptic proteins involved in exocytosis and endocytosis were undetectable in a subset of transgenic boutons ("vacant synapses") with diminished levels in the remainder, suggesting that such diminutions were triggering the overall synaptic pathology. Similar synaptic protein alterations were also retrospectively seen in human pathologic brains, highlighting potential relevance to human disease. Collectively the data suggest a previously unknown cascade of events where pathologic alpha-synuclein leads to a loss of a number of critical presynaptic proteins, thereby inducing functional synaptic deficits.