Animal models in human disease

Proteomics Clin. Appl. 2008, 2, 635–637 635

Animal models in human disease

During recent years, a large variety of proteomics studies utilizing very differentproteomics techniques has resulted in a wealth of information on human disease.Especially animal models for human diseases have yielded clues that may be usefulin elucidating molecular mechanisms and pathways involved in these disorders. Inthis special issue of PROTEOMICS – Clinical Applications you will find a collectionof reviews and research papers dealing with ”animal models in human disease”,providing an overview on current knowledge. Animal models are an important toolfor scientists to investigate human disease, especially in order to conduct time-course studies or when studying early disease. In addition hypothesis-driven experi-mental manipulation of an animal model is permissible which would be impossiblein humans. When compared to humans, animal models usually have a short gen-eration time and a homogenous genetic background, reducing the time frame forexperiments and the amount of variation respectively. This special issue publishesfour reviews which aim to provide an overview on how animal models are used inproteomics research, combining reviews with broad scope (Bousette et al.) and ofvery special aspects of disease (Sultana et al.). The advantages of using animal mod-els as compared to human sample material are discussed in various ways throughoutthe reviews. In the second part of this special issue three research articles providetypical examples of how animal models can be used in proteomics studies of humandisease.

The review of Bousette et al. discusses several proteomics approaches such as 2-Dgel electrophoresis/mass spectrometry as well as gel free approaches and theirapplication to various disorders such as fragile X syndrome, cancer,diabetes, limb girdle muscular dystrophy and African sleeping dis-order. It also stresses the benefits of using animal models over humansamples. Subsequently, post-translational modifications and proteininteractions in disease models are elaborated. The role of diseasemodels in biomarker discovery is evaluated and the creation of stand-ard proteomes in order to compare different disorders is recom-mended and possibilities of its creation are shown. Resjö et al. con-centrate on animal models for a specific disorder – diabetes. Theauthors collected a total of 27 papers, published between 1997 and2007 on both type 1 and type 2 diabetes, providing a good overview ofproteomics approaches used for research into this disorder. The authors also pointout the role of secondary complications associated with diabetes such as cardiomyo-pathy, nephropathy and retinopathy. Li et al. summarize research on animal modelsfor amyotrophic lateral sclerosis (ALS). ALS may occur as sporadic and familial dis-ease. The cause of sporadic disease is still unknown, while familial cases showmutations in the mitochondrial Sod1 gene (mSod1). Mouse models with thesemutations recapitulate the human ALS pathology quite well, and were used in thisreview to delineate a potential mechanism for ALS pathology. Moreover, the potentialof studies investigating cerebrospinal fluid and blood of ALS patients to yield bio-markers is evaluated. The review focuses especially on results obtained by a G93A-

EDITORIAL

Animal models are an importanttool for scientists to investigatehuman disease, especially in orderto conduct time-course studies orwhen studying early disease.

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636 Proteomics Clin. Appl. 2008, 2, 635–637

mSod1 transgenic mouse model with particular emphasis on the total spinal cordproteome. Results are compared with classical non-proteomics research and humandisease. Sultana et al. concentrate in their review on redox proteomics studies of ”invivo” amyloid beta-peptide animal models of Alzheimer’s disease (AD). They inves-tigate the role of oxidative stress in AD. This is a review on a very specific patho-mechanism which is not restricted to AD but is also observed in neurodegenerativedisorders such as Parkinson’s (PD) and Huntington’s disease.

The second part of this special issue consists of three research articles dealingwith three very different diseases, a mouse model for PD, primary torsion dystoniaand sickle cell disease. Collectively, they provide a brief glimpse into just how vari-able and promising the study of diseases by animal models can be.

Gillardon et al. use a mouse model for PD with a mutation in alpha-synuclein(A30P) to study early changes in disease. Mutated alpha-synuclein is a proteinimplicated in familial PD and is found in characteristic intracellular aggregates inaffected neurons – so called Lewy bodies. The authors studied a synaptosomal pro-tein extract from brain samples of this mouse model. Since alpha-synuclein accu-mulates at the presynapse, these extracts were studied for possible pathologicalalterations in the proteome. The protein changes found by the authors resemblefindings in PD patients. Following in-depth investigation using microRNA screen-ing, the authors found one altered microRNA species which is a key regulator ofneurite outgrowth. Recognition sequences for this microRNA were detected onmRNAs of two differentially expressed proteins found in this study. In a study onsickle cell disease Biondani et al. describe a possible implication of heat shock pro-teins in disease pathology. They investigated a time course mimicking the vasoocclusive crisis which may occur in the course of this disorder. Vaso occlusive crisis is acommon painful complication of sickle cell disease in adolescents and adults. Theauthors hypothesize that the heat shock proteins (Hsp) Hsp27 and Hsp70 play anovel role as red blood cell membrane protein protectors and may serve as a newseverity marker for red blood cell damage. Grundmann et al. describe gene expres-sion changes in a mouse model for primary torsion dystonia. In this mouse modelthe Dyt1 gene encoding for the protein TorsinA is mutated. A reduction of thenumber of CAG repeats is responsible for 70% of primary dystonia cases. Theauthors conducted a genome wide microarray study to further elucidate thepathology of the disease. So far it is unknown how TorsinA causes pathology.Importantly, in this study the impact of wild type and mutated TorsinA over-expression on gene expression was investigated in parallel. Interestingly, there werealready changes in expression due to over-expression of ”wild type” TorsinA. Stillmany changes specific to mutant TorsinA were also detected. In addition, theauthors found a large overlap of expression changes caused by ”wild type” andmutant TorsinA.

A bottleneck of proteomics studies is still how to best use the data generated.Employing databases (for a list see http://www.imb-jena.de/jcb/ppi/jcb_ppi_databases.html), gene ontology (GO) and other characteristics, proteins can be groupedaccording to different cellular functions. These can be integrated into known ornovel disease pathways. Since different studies may have investigated the same dis-ease at different time points, pooling all differentially expressed proteins within a

Claus Zabel

Joachim Klose


Proteomics Clin. Appl. 2008, 2, 635–637 637

disease from different studies and different proteomics approaches into a standardproteome (Bousette et al.) may yield an increasingly well-rounded ”picture” for aspecific disorder.

This special issue shows clearly the importance of animal models for the inves-tigation of human disorders. One important goal for already available and futurestudies would be to pool the results and make them publicly available in a compati-ble data format with standardized background information to ensure adequateinformation transfer. In this way researchers do not have to begin from scratch whenstudying human disorders but may ask more specific questions and, e.g., investigatea disease at time points which are of real interest.

We believe that this special issue of PROTEOMICS – Clinical applications pre-sents a powerful summary on how animal models are used in current proteomicsresearch on human disorders which will be useful for established researchers as wellas for those who are new to clinical proteomics.

Claus Zabel

Joachim Klose

Charité – Universitätsmedizin BerlinGermany


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Animal models in human disease